Exploration of Targeted Anti-tumor Therapy

Table 2. Summary of pre-clinical evaluation of pharmacological inhibitors of TPC2, including proposed down-stream mechanisms

Cancer	Cell line(s)	Effects				Mechanism	Ref
Cancer	Cell line(s)	Growth	Cell death	Migration & invasion	Growth in vivo	Mechanism	Ref
Naringenin
Glioma	C6	-	-	-	↓	ROS, cyclin D1, NFκB, CDK4	[118]
	C6	-	-	-	↓	PI3K, PKB	[119]
	U-118MG	-	↑	-	-	-	[108]
	GBM8401	None	↑	↓	-	MMP	[109]
Melanoma	B16F10	↓	↑	-	↓ (lung mets)	Transglutaminase	[110]
	B16F10	↓	↑	-	-	-	[111]
	B16F10, SK- MEL-28	↓	↑	↓	-	ERK1/2, JNK, MAPK, PARP, caspase	[112]
	B16F10	-	-	-	↓	TGFβ-Smad-MMP2	[120]
Breast cancer	MDA-MB-435	↓	-	-	↓ (delayed tumor growth; DMBA rat)	-	[91]
	4T1	None	-	-	↓ (lung mets)	IFN-γ, IL-2	[126]
	MCF-7, T47D, MDA-MB-231	↓	↑	-	-	Caspase, p38	[92]
	MDA-MB-231, MDA-MB-468	-	↑	-	-	-	[93]
	HTB26, HTB132	↓	↑	-	-	Cyclins, caspases, PI3K/Akt pathway, NFκB	[94]
	SKBR3, MDA- MB-231	↓	↑	-	-	HER2	[95]
	4T1	-	-	-	↓ (lung mets)	TGFβ	[127]
	E0771	↓	↑	-	↓ (delayed tumor growth)	AMPK, cyclin D1	[96]
	MDA-MB-231	↓	↑	↓	↓	Mitochondria, NFκB, biotransformation enzymes	[97]
	MCF-7, T47D	-	↑	-	↓	Aromatase	[98]
Colorectal cancer	Azoxymethane rat model	-	-	-	↓	-	[115]
	HCT116	↓	-	-	-	Cell cycle regulatory protein expression	[99]
	SW1116, SW837	↓	↑	-	-	Cyclins, caspases, PI3K/Akt pathway, NFκB	[94]
	HCT116, SW480	↓	-	-	-	Cyclin D1, p38	[100]
	HT29	↓	↑	-	-	Cell cycle and death pathways	[101]
	Caco-2	↓	-	-	-	ROS	[102]
	HCT116, HT29, T84	None	None	-	-	MAPK	[122]
Hepatic carcinoma	HepG2	↓	↑	-	-	P53, caspase	[103]
	NDEA-induced rat model	-	-	-	↓	PCNA, Bcl-2, NFκB, VEGF, MMP	[116]
	NDEA-induced rat model	-	-	-	↓	Antioxidant	[117]
Prostate cancer	PC3, LnCaP	↓	↑	↓	-	ROS, mitochondria	[104]
	PC3	-	-	↓	-	EMT, uPA activity	[128]
	Mat-LyLu	↓	-	↓	-	SCN9A	[105]
Pancreatic cancer	ASPC-1, PANC-1	-	↑	↓	-	EMT	[106]
Pancreatic cancer	SNU-213	-	↑	-	-	ROS	[107]
Lung cancer	NRG mice model	-	-	-	↓	CYP1A1, NFκB, PCNA	[121]
	A549	↓	-	↓	-	MMP-2/9, Akt	[113]
	A549	↓	↑	↓	-	Caspase, MMP	[114]
	LLC	-	-	-	↓	TGFβ-Smad-MMP2	[120]
Tetrandrine
AML	U937	↓	↑	-	-	Caspase, JNK, PKC-δ	[129]
	NB4	↓	-	-	↓	ROS, Notch-1	[130]
	K562, 6133 MPL^W515L	↓	↑	-	-	P21, p27, ROS, Notch-1 signaling	[131]
	HL60, K562, U937, THP-1	↓	↑	-	↓	ROS, c-myc	[132]
Glioma	RT-2	↓	↑	-	↓	-	[55]
	U-87	↓	↑	↓	-	ADAM17, PI3K/Akt signaling pathway	[133]
	U-87, U251, SWO- 38	↓	↑	-	↓	STAT3	[56]
	U-87, U251	↓ (Neurosphere formation)	↑	-	-	β-catenin, PARP, Bcl-2	[134]
	U-87, U251	↓	-	-	-	ERK	[135]
	GBM 8401	-	-	↓	-	MMP-2/9, NFκB, Akt, EGFR, E/N-cadherin	[136]
Neuroblastoma	Neuro2a	↓	↑	-	-	ROS	[137]
Neuroblastoma	SHSY5Y	-	↑	-	-	-	[138]
Osteosarcoma	U-20S, MG-63	-	↑	-	-	Apaf-1, Bid, Bax, Bcl-2	[139]
Osteosarcoma	143B	↓	↑	-	↓	PTEN, PCNA	[140]
Nasopharyngeal carcinoma	CNE	-	↑	-	-	Bax/Bcl-2	[141]
Nasopharyngeal carcinoma	NPC-TW076	↓	↑	-	-	Endoplasmic reticulum stress	[142]
Lung cancer	A549	↓	↑	-	-	Akt, ERK	[143]
Lung cancer	A549	↓	↑	-	-	VEGF/HIF-1/ICAM-1	[144]
Oral cancer	SAS	-	↑	-	-	PARP, caspase	[145]
	HSC-3	-	↑	-	-	PARP, caspase, beclin-1/LC3-1/II signaling	[146]
	CAL27	-	↑	-	-	ROS, caspase, Beclin-1 signaling	[147]
Gastric cancer	BGC-823	-	↑	-	-	Caspase/mitochondria- mediated	[148]
Gastric cancer	HGC-27	-	↑	-	-	PARP, caspase, Beclin-1/LC3-II/p62, Akt/mTOR	[67]
Prostate cancer	DU145, PC3	↓	↑	-	-	ROS, JNK1/2	[149]
	DU145, PC3	↓	↑	↓	-	PARP, PI3K/Akt	[150]
	DU145, PC3	-	-	↓	-	Akt/mTOR/MMP-9 signaling	[151]
Bladder cancer	5637, T24	-	↑	-	-	Caspase/mitochondria- mediated	[152]
Bladder cancer	5637, T24	-	-	↓	-	Inducing MET through downregulation of Gli-1	[153]
Breast cancer	SUM-149, SUM-159, sphere (patient sample)	↓	-	-	-	-	[154]
	4T1	-	-	-	↓ (lung mets)	ERK, NFκB, VEGF, HIF-1α, integrin β5 and ICAM-1	[57]
	MCF-7	-	↓	-	-	PKCα, caspase	[155]
	MDA-MB-231	↓	↑	-	-	Beclin-1/LC3-I/LC3-II and PI3K/Akt/mTOR signaling pathways	[68]
	MDA-MB-231	-	↑	-	↓	Bcl-2, Bax, PARP, caspase	[156]
Renal cell carcinoma	786-O, 769-P, ACHN	↓	↑	-	-	Caspase, p21 and p27	[157]
Renal cell carcinoma	786-O, 769-P	-	-	↓	-	MMP-9, PI3K/Akt, NFκB	[158]
Hepatic carcinoma	HepG2	↓	↑	-	-	Caspase	[159]
	HepG2	↓	↑	-	-	Caspase	[160]
	Hep G2, Hep 3B, PLC/PRF/5	↓	-	-	-	-	[161]
	HepG2, Huh7	-	↑	-	↓	ROS, Akt	[162]
	Huh-7	-	-	-	↓	ROS, ERK	[163]
	Huh-7	↓	↑	-	-	Caspase, PARP	[164]
	Huh7, SMMC- 7721, HepG2, PLC/PRF/5, MHCC97H, SK- Hep-1, SNU398	↓	-	-	-	CaMKII	[165]
Colorectal cancer	CT-26	-	↑	-	↓ (lung mets)	-	[166]
	HT-29	↓	↑	-	-	PI3K/Akt/GSK3β, PARP	[167]
	CT-26	-	↑	-	↓	P38 MAPK	[168]
	SW480, HCT116	↓	↑	↓	↓	Wnt/β-catenin,	[169]
	LoVo	↓	↑	-	↓	IGFBP-5, Wnt/β-catenin	[170]
	HCT116	↓	↑	↓	-	MMP-2, EMT	[171]
Cervical cancer	SiHa	↓	↑	↓	↓	Caspase, MMP-2, MMP-9	[172]
Gallbladder cancer	SGC-996	↓	↑	-	-	Caspase, PARP, mitochondria	[173]
Pancreatic cancer	PaCa	↓	-	-	↓	P21, p27, cyclin D	[174]
Ovarian cancer	OVCAR-3, A2780	↓	↑	-	↓	Wnt, E-cadherin, cyclin D, c-myc	[175]
Ned-19
Bladder cancer	T24	-	-	↓	-	Endocytic recycling	[51]
Hepatic carcinoma	Huh7	-	-	↓	-	Endocytic recycling	[51]
Breast cancer	4T1	-	-	↓	↓	Endocytic recycling	[51]
Melanoma	B16	↓	↑	↓	↓	VEGF	[176]
Colorectal cancer	Patient samples	↓	-	-	-	ERK, Akt	[177]
Verapamil
Breast cancer	ZR-751A	↑	-	-	-	-	[178]
Colorectal cancer	LoVo	↑	-	-	-	-	[178]
AML	Patient samples	↓	-	-	-	-	[179]
AML	Patient samples	↓	-	-	-	-	[180]
CML	Patient samples	None	-	-	-	-	[180]

Return to article view

ADAM17: ADAM metallopeptidase domain 17; AML: acute myeloid leukaemia; Bcl-2: B-cell lymphoma-2; CaMKII: calcium/calmodulin-stimulated protein kinase II; CDK4: cyclin-dependent kinase 4; CML: chronic myeloid leukaemia; DMBA: 7,12-dimethylbenz[a]anthracene; EGFR: epidermal growth factor receptor; EMT: epithelial to mesenchymal transition; ERK1: extracellular signal-regulated kinase 1; GSK3β: glycogen synthase kinase 3 β; HER2: human epidermal growth factor receptor 2; HIF-1: hypoxia inducible factor 1; ICAM-1: intracellular adhesion molecule 1; IFN: interferon; IGFBP: insulin-like growth factor binding protein; IL-2: interleukin-2; MET: mesenchymal to epithelial transition; mets: metastases; NDEA: N-nitrosodiethylamine; PARP: polyadenosine-diphosphate-ribose polymerase; PCNA: proliferating cell nuclear antigen; PKB: protein kinase B; PI3K: phosphoinositide-3-kinase; PTEN: phosphatase and tensin homolog; Ref: reference; ROS: reactive oxygen species; SCN9A: sodium voltage-gated channel α subunit 9; STAT3: signal transducer and activator of transcription 3; TGFβ: transforming growth factor β; uPA: urokinase type plasminogen activator; ↓: decreased effects; ↑: increased or induced effects; -: not examined

Declarations

Author contributions

All authors contributed to the drafting and editing of the manuscript. DLB and DZT created the figures. KAS and LFL contributed conception and design of the review. KAS, LFL, DLB and DZT contributed to manuscript revision, read, and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Brzozowski JS, Skelding KA. The multi-functional calcium/calmodulin stimulated protein kinase (CaMK) family: emerging targets for anti-cancer therapeutic intervention. Pharmaceuticals (Basel). 2019;12:8. [DOI] [PubMed] [PMC]

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. [DOI]

Zhu MX, Ma J, Parrington J, Calcraft PJ, Galione A, Evans AM. Calcium signaling via two-pore channels: local or global, that is the question. Am J Physiol Cell Physiol. 2010;298:C430–41. [DOI] [PubMed] [PMC]

de Duve C. Lysosomes, a new group of cytoplasmic particles. In: Hayashi T, editor. Subcellular particles. New York: Ronald Press Co; 1959. pp. 129–59.

Repnik U, Cesen MH, Turk B. The endolysosomal system in cell death and survival. Cold Spring Harb Perspect Biol. 2013;5:a008755. [DOI] [PubMed] [PMC]

Kintzer AF, Stroud RM. On the structure and mechanism of two-pore channels. FEBS J. 2018;285:233–43. [DOI] [PubMed] [PMC]

Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, et al. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature. 2009;459:596–600. [DOI] [PubMed] [PMC]

Zong X, Schieder M, Cuny H, Fenske S, Gruner C, Rotzer K, et al. The two-pore channel TPCN2 mediates NAADP-dependent Ca(2+)-release from lysosomal stores. Pflugers Arch. 2009;458:891–9. [DOI] [PubMed] [PMC]

Wang X, Zhang X, Dong XP, Samie M, Li X, Cheng X, et al. TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes. Cell. 2012;151:372–83. [DOI] [PubMed] [PMC]

10.

Cang C, Zhou Y, Navarro B, Seo YJ, Aranda K, Shi L, et al. mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state. Cell. 2013;152:778–90. [DOI] [PubMed] [PMC]

11.

Jha A, Ahuja M, Patel S, Brailoiu E, Muallem S. Convergent regulation of the lysosomal two-pore channel-2 by Mg²⁺, NAADP, PI(3,5)P₂ and multiple protein kinases. EMBO J. 2014;33:501–11. [DOI] [PubMed] [PMC]

12.

Brailoiu E, Rahman T, Churamani D, Prole DL, Brailoiu GC, Hooper R, et al. An NAADP-gated two-pore channel targeted to the plasma membrane uncouples triggering from amplifying Ca²⁺ signals. J Biol Chem. 2010;285:38511–6. [DOI] [PubMed] [PMC]

13.

Brailoiu E, Churamani D, Cai X, Schrlau MG, Brailoiu GC, Gao X, et al. Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling. J Cell Biol. 2009;186:201–9. [DOI] [PubMed] [PMC]

14.

She J, Zeng W, Guo J, Chen Q, Bai XC, Jiang Y. Structural mechanisms of phospholipid activation of the human TPC2 channel. Elife. 2019;8:e45222. [DOI] [PubMed] [PMC]

15.

Kintzer AF, Stroud RM. Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana. Nature. 2016;531:258–62. [DOI] [PubMed] [PMC]

16.

Rietdorf K, Funnell TM, Ruas M, Heinemann J, Parrington J, Galione A. Two-pore channels form homo- and heterodimers. J Biol Chem. 2011;286:37058–62. [DOI] [PubMed] [PMC]

17.

Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem. 2004;25:1605–12. [DOI] [PubMed]

18.

Lin-Moshier Y, Keebler MV, Hooper R, Boulware MJ, Liu X, Churamani D, et al. The two-pore channel (TPC) interactome unmasks isoform-specific roles for TPCs in endolysosomal morphology and cell pigmentation. Proc Natl Acad Sci U S A. 2014;111:13087–92. [DOI] [PubMed] [PMC]

19.

Yamaguchi S, Jha A, Li Q, Soyombo AA, Dickinson GD, Churamani D, et al. Transient receptor potential mucolipin 1 (TRPML1) and two-pore channels are functionally independent organellar ion channels. J Biol Chem. 2011;286:22934–42. [DOI] [PubMed] [PMC]

20.

Gomez-Suaga P, Luzon-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, et al. Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet. 2012;21:511–25. [DOI] [PubMed] [PMC]

21.

Lopez J, Dionisio N, Berna-Erro A, Galan C, Salido GM, Rosado JA. Two-pore channel 2 (TPC2) modulates store-operated Ca(2+) entry. Biochim Biophys Acta. 2012;1823:1976–83. [DOI] [PubMed]

22.

Lam AKM, Galione A, Lai FA, Zissimopoulos S. Hax-1 identified as a two-pore channel (TPC)-binding protein. FEBS Lett. 2013;587:3782–6. [DOI] [PubMed]

23.

Sharp TV, Wang HW, Koumi A, Hollyman D, Endo Y, Ye H, et al. K15 protein of Kaposi’s sarcoma-associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function. J Virol. 2002;76:802–16. [DOI] [PubMed] [PMC]

24.

Zhang J, Guan X, Shah K, Yan J. Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles. Nat Commun. 2021;12:4739. [DOI] [PubMed] [PMC]

25.

Webb SE, Kelu JJ, Miller AL. Role of two-pore channels in embryonic development and cellular differentiation. Cold Spring Harb Perspect Biol. 2020;12:a035170. [DOI] [PubMed] [PMC]

26.

Marchant JS, Patel S. Two-pore channels at the intersection of endolysosomal membrane traffic. Biochem Soc Trans. 2015;43:434–41. [DOI] [PubMed] [PMC]

27.

Ramos I, Reich A, Wessel GM. Two-pore channels function in calcium regulation in sea star oocytes and embryos. Development. 2014;141:4598–609. [DOI] [PubMed] [PMC]

28.

Grimm C, Holdt LM, Chen CC, Hassan S, Muller C, Jors S, et al. High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. Nat Commun. 2014;5:4699. [DOI] [PubMed]

29.

Sun W, Yue J. TPC2 mediates autophagy progression and extracellular vesicle secretion in cancer cells. Exp Cell Res. 2018;370:478–89. [DOI] [PubMed]

30.

Hamilton A, Zhang Q, Salehi A, Willems M, Knudsen JG, Ringgaard AK, et al. Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca²⁺ mobilization from acidic stores in pancreatic α-Cells. Diabetes. 2018;67:1128–39. [DOI] [PubMed] [PMC]

31.

Capel RA, Bolton EL, Lin WK, Aston D, Wang Y, Liu W, et al. Two-pore channels (TPC2s) and nicotinic acid adenine dinucleotide phosphate (NAADP) at lysosomal-sarcoplasmic reticular junctions contribute to acute and chronic β-adrenoceptor signaling in the heart. J Biol Chem. 2015;290:30087–98. [DOI] [PubMed] [PMC]

32.

Davis LC, Morgan AJ, Galione A. NAADP-regulated two-pore channels drive phagocytosis through endo-lysosomal Ca²⁺ nanodomains, calcineurin and dynamin. EMBO J. 2020;39:e104058. [DOI] [PubMed] [PMC]

33.

Favia A, Desideri M, Gambara G, D'Alessio A, Ruas M, Esposito B, et al. VEGF-induced neoangiogenesis is mediated by NAADP and two-pore channel-2-dependent Ca²⁺ signaling. Proc Natl Acad Sci U S A. 2014;111:E4706–15. [DOI] [PubMed] [PMC]

34.

Davis LC, Morgan AJ, Chen JL, Snead CM, Bloor-Young D, Shenderov E, et al. NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing. Curr Biol. 2012;22:2331–7. [DOI] [PubMed] [PMC]

35.

Sakurai Y, Kolokoltsov AA, Chen CC, Tidwell MW, Bauta WE, Klugbauer N, et al. Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science. 2015;347:995–8. [DOI] [PubMed] [PMC]

36.

Millet JK, Whittaker GR. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proc Natl Acad Sci U S A. 2014;111:15214–9. [DOI] [PubMed] [PMC]

37.

Gunaratne GS, Yang Y, Li F, Walseth TF, Marchant JS. NAADP-dependent Ca²⁺ signaling regulates Middle East respiratory syndrome-coronavirus pseudovirus translocation through the endolysosomal system. Cell Calcium. 2018;75:30–41. [DOI] [PubMed] [PMC]

38.

Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020;11:1620. [DOI] [PubMed] [PMC]

39.

Khan N, Halcrow PW, Lakpa KL, Afghah Z, Miller NM, Dowdy SF, et al. Two-pore channels regulate Tat endolysosome escape and Tat-mediated HIV-1 LTR transactivation. FASEB J. 2020;34:4147–62. [DOI] [PubMed] [PMC]

40.

Hockey LN, Kilpatrick BS, Eden ER, Lin-Moshier Y, Brailoiu GC, Brailoiu E, et al. Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition. J Cell Sci. 2015;128:232–8. [DOI] [PubMed] [PMC]

41.

Tong BCK, Wu AJ, Huang AS, Dong R, Malampati S, Iyaswamy A, et al. Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease. Autophagy. 2021;[Epub ahead of print]. [DOI] [PubMed]

42.

Garcia-Rua V, Otero MF, Lear PV, Rodriguez-Penas D, Feijoo-Bandin S, Noguera-Moreno T, et al. Increased expression of fatty-acid and calcium metabolism genes in failing human heart. PLoS One. 2012;7:e37505. [DOI] [PubMed] [PMC]

43.

Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Pache L, et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature. 2020;586:113–9. [DOI] [PubMed] [PMC]

44.

Netcharoensirisuk P, Abrahamian C, Tang R, Chen CC, Rosato AS, Beyers W, et al. Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2. Sci Rep. 2021;11:8515. [DOI] [PubMed] [PMC]

45.

Muller M, Gerndt S, Chao YK, Zisis T, Nguyen ONP, Gerwien A, et al. Gene editing and synthetically accessible inhibitors reveal role for TPC2 in HCC cell proliferation and tumor growth. Cell Chem Biol. 2021;28:1119–31.e27. [DOI] [PubMed]

46.

Jiang Y, Zhou Y, Peng G, Tian H, Pan D, Liu L, et al. Two-pore channels mediated receptor-operated Ca²⁺ entry in pulmonary artery smooth muscle cells in response to hypoxia. Int J Biochem Cell Biol. 2018;97:28–35. [DOI] [PubMed]

47.

D’Amore A, Hanbashi AA, Di Agostino S, Palombi F, Sacconi A, Voruganti A, et al. Loss of two-pore channel 2 (TPC2) expression increases the metastatic traits of melanoma cells by a mechanism involving the hippo signalling pathway and store-operated calcium entry. Cancers (Basel). 2020;12:2391. [DOI] [PubMed] [PMC]

48.

Aley PK, Mikolajczyk AM, Munz B, Churchill GC, Galione A, Berger F. Nicotinic acid adenine dinucleotide phosphate regulates skeletal muscle differentiation via action at two-pore channels. Proc Natl Acad Sci U S A. 2010;107:19927–32. [DOI] [PubMed] [PMC]

49.

Notomi T, Ezura Y, Noda M. Identification of two-pore channel 2 as a novel regulator of osteoclastogenesis. J Biol Chem. 2012;287:35057–64. [DOI] [PubMed] [PMC]

50.

Zhang ZH, Lu YY, Yue J. Two pore channel 2 differentially modulates neural differentiation of mouse embryonic stem cells. PLoS One. 2013;8:e66077. [DOI] [PubMed] [PMC]

51.

Nguyen ONP, Grimm C, Schneider LS, Chao YK, Atzberger C, Bartel K, et al. Two-pore channel function is crucial for the migration of invasive cancer cells. Cancer Res. 2017;77:1427–38. [DOI] [PubMed]

52.

Hwangbo C, Park J, Lee JH. mda-9/Syntenin protein positively regulates the activation of Akt protein by facilitating integrin-linked kinase adaptor function during adhesion to type I collagen. J Biol Chem. 2011;286:33601–12. [DOI] [PubMed] [PMC]

53.

Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13:871–82. [DOI] [PubMed] [PMC]

54.

Itatani Y, Kawada K, Yamamoto T, Sakai Y. Resistance to anti-angiogenic therapy in cancer-alterations to anti-VEGF pathway. Int J Mol Sci. 2018;19:1232. [DOI] [PubMed] [PMC]

55.

Chen Y, Chen JC, Tseng SH. Tetrandrine suppresses tumor growth and angiogenesis of gliomas in rats. Int J Cancer. 2009;124:2260–9. [DOI] [PubMed]

56.

Ma JW, Zhang Y, Li R, Ye JC, Li HY, Zhang YK, et al. Tetrandrine suppresses human glioma growth by inhibiting cell survival, proliferation and tumour angiogenesis through attenuating STAT3 phosphorylation. Eur J Pharmacol. 2015;764:228–39. [DOI] [PubMed]

57.

Gao JL, Ji X, He TC, Zhang Q, He K, Zhao Y, et al. Tetrandrine suppresses cancer angiogenesis and metastasis in 4T1 tumor bearing mice. Evid Based Complement Alternat Med. 2013;2013:265061. [DOI] [PubMed] [PMC]

58.

Pafumi I, Festa M, Papacci F, Lagostena L, Giunta C, Gutla V, et al. Naringenin impairs two-pore channel 2 activity and inhibits VEGF-induced angiogenesis. Sci Rep. 2017;7:5121. [DOI] [PubMed] [PMC]

59.

Li Y, Schon C, Chen CC, Yang Z, Liegl R, Murenu E, et al. TPC2 promotes choroidal angiogenesis and inflammation in a mouse model of neovascular age-related macular degeneration. Life Sci Alliance. 2021;4:e202101047. [DOI] [PubMed] [PMC]

60.

Huang T, Song X, Yang Y, Wan X, Alvarez AA, Sastry N, et al. Autophagy and hallmarks of cancer. Crit Rev Oncog. 2018;23:247–67. [DOI] [PubMed] [PMC]

61.

Singh SS, Vats S, Chia AY, Tan TZQ, Deng S, Ong MS, et al. Dual role of autophagy in hallmarks of cancer. Oncogene. 2018;37:1142–58. [DOI] [PubMed]

62.

Pereira GJS, Hirata H, Fimia GM, do Carmo LG, Bincoletto C, Han SW, et al. Nicotinic acid adenine dinucleotide phosphate (NAADP) regulates autophagy in cultured astrocytes. J Biol Chem. 2011;286:27875–81. [DOI] [PubMed] [PMC]

63.

Pereira GJS, Antonioli M, Hirata H, Ureshino RP, Nascimento AR, Bincoletto C, et al. Glutamate induces autophagy via the two-pore channels in neural cells. Oncotarget. 2017;8:12730–40. [DOI] [PubMed] [PMC]

64.

Garcia-Rua V, Feijoo-Bandin S, Rodriguez-Penas D, Mosquera-Leal A, Abu-Assi E, Beiras A, et al. Endolysosomal two-pore channels regulate autophagy in cardiomyocytes. J Physiol. 2016;594:3061–77. [DOI] [PubMed] [PMC]

65.

Lu Y, Hao B, Graeff R, Yue J. NAADP/TPC2/Ca(2+) Signaling inhibits autophagy. Commun Integr Biol. 2013;6:e27595. [DOI] [PubMed] [PMC]

66.

Lin PH, Duann P, Komazaki S, Park KH, Li H, Sun M, et al. Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling. J Biol Chem. 2015;290:3377–89. [DOI] [PubMed] [PMC]

67.

Bai XY, Liu YG, Song W, Li YY, Hou DS, Luo HM, et al. Anticancer activity of tetrandrine by inducing pro-death apoptosis and autophagy in human gastric cancer cells. J Pharm Pharmacol. 2018;70:1048–58. [DOI] [PubMed]

68.

Guo Y, Pei X. Tetrandrine-Induced Autophagy in MDA-MB-231 Triple-negative breast cancer cell through the inhibition of PI3K/AKT/mTOR signaling. Evid Based Complement Alternat Med. 2019;2019:7517431. [DOI] [PubMed] [PMC]

69.

Kou B, Liu W, Xu X, Yang Y, Yi Q, Guo F, et al. Autophagy induction enhances tetrandrine-induced apoptosis via the AMPK/mTOR pathway in human bladder cancer cells. Oncol Rep. 2017;38:3137–43. [DOI] [PubMed]

70.

Kosiniak-Kamysz A, Marczakiewicz-Lustig A, Marcinska M, Skowron M, Wojas-Pelc A, Pospiech E, et al. Increased risk of developing cutaneous malignant melanoma is associated with variation in pigmentation genes and VDR, and may involve epistatic effects. Melanoma Res. 2014;24:388–96. [DOI] [PubMed]

71.

Pho LN, Leachman SA. Genetics of pigmentation and melanoma predisposition. G Ital Dermatol Venereol. 2010;145:37–45. [PubMed]

72.

Alharbi AF, Parrington J. The role of genetic polymorphisms in endolysosomal ion channels TPC2 and P2RX4 in cancer pathogenesis, prognosis, and diagnosis: a genetic association in the UK Biobank. NPJ Genom Med. 2021;6:58. [DOI] [PubMed] [PMC]

73.

Ambrosio AL, Boyle JA, Aradi AE, Christian KA, Di Pietro SM. TPC2 controls pigmentation by regulating melanosome pH and size. Proc Natl Acad Sci U S A. 2016;113:5622–7. [DOI] [PubMed] [PMC]

74.

Howarth KD, Mirza T, Cooke SL, Chin SF, Pole JC, Turro E, et al. NRG1 fusions in breast cancer. Breast Cancer Res. 2021;23:3. [DOI] [PubMed] [PMC]

75.

Hodgson A, Swanson D, Tang S, Dickson BC, Turashvili G. Gene fusions characterize a subset of uterine cellular leiomyomas. Genes Chromosomes Cancer. 2020;[Epub ahead of print]. [DOI] [PubMed]

76.

Wilkerson PM, Reis-Filho JS. The 11q13-q14 amplicon: clinicopathological correlations and potential drivers. Genes Chromosomes Cancer. 2013;52:333–55. [DOI] [PubMed]

77.

Sugahara K, Michikawa Y, Ishikawa K, Shoji Y, Iwakawa M, Shibahara T, et al. Combination effects of distinct cores in 11q13 amplification region on cervical lymph node metastasis of oral squamous cell carcinoma. Int J Oncol. 2011;39:761–9. [DOI]

78.

Huang X, Godfrey TE, Gooding WE, McCarty KS Jr, Gollin SM. Comprehensive genome and transcriptome analysis of the 11q13 amplicon in human oral cancer and synteny to the 7F5 amplicon in murine oral carcinoma. Genes Chromosomes Cancer. 2006;45:1058–69. [DOI] [PubMed]

79.

Jahidin AH, Stewart TA, Thompson EW, Roberts-Thomson SJ, Monteith GR. Differential effects of two-pore channel protein 1 and 2 silencing in MDA-MB-468 breast cancer cells. Biochem Biophys Res Commun. 2016;477:731–6. [DOI] [PubMed]

80.

Li F, Ji JP, Xu Y, Liu RL. Identification a novel set of 6 differential expressed genes in prostate cancer that can potentially predict biochemical recurrence after curative surgery. Clin Transl Oncol. 2019;21:1067–75. [DOI] [PubMed]

81.

Shivakumar M, Lee Y, Bang L, Garg T, Sohn KA, Kim D. Identification of epigenetic interactions between miRNA and DNA methylation associated with gene expression as potential prognostic markers in bladder cancer. BMC Med Genomics. 2017;10:30. [DOI] [PubMed] [PMC]

82.

Kocarnik JM, Park SL, Han J, Dumitrescu L, Cheng I, Wilkens LR, et al. Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the population architecture using genomics and epidemiology (PAGE) study. PLoS One. 2015;10:e0120491. [DOI] [PubMed] [PMC]

83.

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021;49:D1388–95. [DOI] [PubMed] [PMC]

84.

Salehi B, Fokou PVT, Sharifi-Rad M, Zucca P, Pezzani R, Martins N, et al. The therapeutic potential of naringenin: a review of clinical trials. Pharmaceuticals (Basel). 2019;12:11. [DOI] [PubMed] [PMC]

85.

Feng XL, Zhan XX, Zuo LSY, Mo XF, Zhang X, Liu KY, et al. Associations between serum concentration of flavonoids and breast cancer risk among Chinese women. Eur J Nutr. 2021;60:1347–62. [DOI] [PubMed]

86.

Khan N, Afaq F, Mukhtar H. Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal. 2008;10:475–510. [DOI] [PubMed]

87.

Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84. [DOI] [PubMed]

88.

Le Marchand L, Murphy SP, Hankin JH, Wilkens LR, Kolonel LN. Intake of flavonoids and lung cancer. J Natl Cancer Inst. 2000;92:154–60. [DOI] [PubMed]

89.

Vitelli Storelli F, Molina AJ, Zamora-Ros R, Fernandez-Villa T, Roussou V, Romaguera D, et al. Flavonoids and the risk of gastric cancer: an exploratory case-control study in the MCC-Spain study. Nutrients. 2019;11:967. [DOI] [PubMed] [PMC]

90.

Pang X, Fu W, Wang J, Kang, Xu L, Zhao Y, et al. Identification of estrogen receptor α antagonists from natural products via in vitro and in silico approaches. Oxid Med Cell Longev. 2018;2018:6040149. [DOI] [PubMed] [PMC]

91.

So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer. 1996;26:167–81. [DOI] [PubMed]

92.

Bulzomi P, Bolli A, Galluzzo P, Acconcia F, Ascenzi P, Marino M. The naringenin-induced proapoptotic effect in breast cancer cell lines holds out against a high bisphenol a background. IUBMB Life. 2012;64:690–6. [DOI] [PubMed]

93.

Ayob Z, Mohd Bohari SP, Abd Samad A, Jamil S. Cytotoxic activities against breast cancer cells of local justicia gendarussa crude extracts. Evid Based Complement Alternat Med. 2014;2014:732980. [DOI] [PubMed] [PMC]

94.

Abaza MSI, Orabi KY, Al-Quattan E, Al-Attiyah RJ. Growth inhibitory and chemo-sensitization effects of naringenin, a natural flavanone purified from Thymus vulgaris, on human breast and colorectal cancer. Cancer Cell Int. 2015;15:46. [DOI] [PubMed] [PMC]

95.

Chandrika BB, Steephan M, Kumar TRS, Sabu A, Haridas M. Hesperetin and naringenin sensitize HER2 positive cancer cells to death by serving as HER2 tyrosine kinase inhibitors. Life Sci. 2016;160:47–56. [DOI] [PubMed]

96.

Ke JY, Banh T, Hsiao YH, Cole RM, Straka SR, Yee LD, et al. Citrus flavonoid naringenin reduces mammary tumor cell viability, adipose mass, and adipose inflammation in obese ovariectomized mice. Mol Nutr Food Res. 2017;61:1600934. [DOI] [PubMed]

97.

Zhao Z, Jin G, Ge Y, Guo Z. Naringenin inhibits migration of breast cancer cells via inflammatory and apoptosis cell signaling pathways. Inflammopharmacology. 2019;27:1021–36. [DOI] [PubMed]

98.

El-Kersh DM, Ezzat SM, Salama MM, Mahrous EA, Attia YM, Ahmed MS, et al. Anti-estrogenic and anti-aromatase activities of citrus peels major compounds in breast cancer. Sci Rep. 2021;11:7121. [DOI] [PubMed] [PMC]

99.

Woo Y, Shin SY, Hyun J, Lee SD, Lee YH, Lim Y. Flavanones inhibit the clonogenicity of HCT116 cololectal cancer cells. Int J Mol Med. 2012;29:403–8.

100.

Song HM, Park GH, Eo HJ, Lee JW, Kim MK, Lee JR, et al. Anti-proliferative effect of naringenin through p38-dependent downregulation of cyclin D1 in human colorectal cancer cells. Biomol Ther (Seoul). 2015;23:339–44. [DOI] [PubMed] [PMC]

101.

Moreno-Jimenez MR, Lopez-Barraza R, Cervantes-Cardoza V, Perez-Ramirez IF, Reyna-Rojas JA, Gallegos-Infante JA, et al. Mechanisms associated to apoptosis of cancer cells by phenolic extracts from two canned common beans varieties (Phaseolus vulgaris L.). J Food Biochem. 2019;43:e12680. [DOI] [PubMed]

102.

Storniolo CE, Sacanella I, Lamuela-Raventos RM, Moreno JJ. Bioactive compounds of Mediterranean cooked tomato sauce (sofrito) modulate intestinal epithelial cancer cell growth through oxidative stress/arachidonic acid cascade regulation. ACS Omega. 2020;5:17071–7. [DOI] [PubMed] [PMC]

103.

Arul D, Subramanian P. Naringenin (citrus flavonone) induces growth inhibition, cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. Pathol Oncol Res. 2013;19:763–70. [DOI] [PubMed]

104.

Lim W, Park S, Bazer FW, Song G. Naringenin-induced apoptotic cell death in prostate cancer cells is mediated via the PI3K/AKT and MAPK signaling pathways. J Cell Biochem. 2017;118:1118–31. [DOI] [PubMed]

105.

Gumushan Aktas H, Akgun T. Naringenin inhibits prostate cancer metastasis by blocking voltage-gated sodium channels. Biomed Pharmacother. 2018;106:770–5. [DOI] [PubMed]

106.

Lou C, Zhang F, Yang M, Zhao J, Zeng W, Fang X, et al. Naringenin decreases invasiveness and metastasis by inhibiting TGF-β-induced epithelial to mesenchymal transition in pancreatic cancer cells. PLoS One. 2012;7:e50956. [DOI] [PubMed] [PMC]

107.

Park HJ, Choi YJ, Lee JH, Nam MJ. Naringenin causes ASK1-induced apoptosis via reactive oxygen species in human pancreatic cancer cells. Food Chem Toxicol. 2017;99:1–8. [DOI] [PubMed]

108.

Stompor M, Uram L, Podgorski R. In vitro effect of 8-prenylnaringenin and naringenin on fibroblasts and glioblastoma cells-cellular accumulation and cytotoxicity. Molecules. 2017;22:1092. [DOI] [PubMed] [PMC]

109.

Chen YY, Chang YM, Wang KY, Chen PN, Hseu YC, Chen KM, et al. Naringenin inhibited migration and invasion of glioblastoma cells through multiple mechanisms. Environ Toxicol. 2019;34:233–9. [DOI] [PubMed]

110.

Lentini A, Forni C, Provenzano B, Beninati S. Enhancement of transglutaminase activity and polyamine depletion in B16-F10 melanoma cells by flavonoids naringenin and hesperitin correlate to reduction of the in vivo metastatic potential. Amino Acids. 2007;32:95–100. [DOI] [PubMed]

111.

Nasr Bouzaiene N, Chaabane F, Sassi A, Chekir-Ghedira L, Ghedira K. Effect of apigenin-7-glucoside, genkwanin and naringenin on tyrosinase activity and melanin synthesis in B16F10 melanoma cells. Life Sci. 2016;144:80–5. [DOI] [PubMed]

112.

Choi J, Lee DH, Jang H, Park SY, Seol JW. Naringenin exerts anticancer effects by inducing tumor cell death and inhibiting angiogenesis in malignant melanoma. Int J Med Sci. 2020;17:3049–57. [DOI] [PubMed] [PMC]

113.

Chang HL, Chang YM, Lai SC, Chen KM, Wang KC, Chiu TT, et al. Naringenin inhibits migration of lung cancer cells via the inhibition of matrix metalloproteinases-2 and -9. Exp Ther Med. 2017;13:739–44. [DOI] [PubMed] [PMC]

114.

Shi X, Luo X, Chen T, Guo W, Liang C, Tang S, et al. Naringenin inhibits migration, invasion, induces apoptosis in human lung cancer cells and arrests tumour progression in vitro. J Cell Mol Med. 2021;25:2563–71. [DOI] [PubMed] [PMC]

115.

Leonardi T, Vanamala J, Taddeo SS, Davidson LA, Murphy ME, Patil BS, et al. Apigenin and naringenin suppress colon carcinogenesis through the aberrant crypt stage in azoxymethane-treated rats. Exp Biol Med (Maywood). 2010;235:710–7. [DOI] [PubMed] [PMC]

116.

Subramanian P, Arul D. Attenuation of NDEA-induced hepatocarcinogenesis by naringenin in rats. Cell Biochem Funct. 2013;31:511–7. [DOI] [PubMed]

117.

Arul D, Subramanian P. Inhibitory effect of naringenin (citrus flavonone) on N-nitrosodiethylamine induced hepatocarcinogenesis in rats. Biochem Biophys Res Commun. 2013;434:203–9. [DOI] [PubMed]

118.

Sabarinathan D, Mahalakshmi P, Vanisree AJ. Naringenin, a flavanone inhibits the proliferation of cerebrally implanted C6 glioma cells in rats. Chem Biol Interact. 2011;189:26–36. [DOI] [PubMed]

119.

Sabarinathan D, Vanisree AJ. Plausible role of naringenin against cerebrally implanted C6 glioma cells in rats. Mol Cell Biochem. 2013;375:171–8. [DOI] [PubMed]

120.

Lian GY, Wang QM, Mak TS, Huang XR, Yu XQ, Lan HY. Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with asiatic acid and naringenin. Mol Ther Oncolytics. 2021;20:277–89. [DOI] [PubMed] [PMC]

121.

Bodduluru LN, Kasala ER, Madhana RM, Barua CC, Hussain MI, Haloi P, et al. Naringenin ameliorates inflammation and cell proliferation in benzo(a)pyrene induced pulmonary carcinogenesis by modulating CYP1A1, NFκB and PCNA expression. Int Immunopharmacol. 2016;30:102–10. [DOI] [PubMed]

122.

Fernandez J, Silvan B, Entrialgo-Cadierno R, Villar CJ, Capasso R, Uranga JA, et al. Antiproliferative and palliative activity of flavonoids in colorectal cancer. Biomed Pharmacother. 2021;143:112241. [DOI] [PubMed]

123.

Erdogan S, Doganlar O, Doganlar ZB, Turkekul K. Naringin sensitizes human prostate cancer cells to paclitaxel therapy. Prostate Int. 2018;6:126–35. [DOI] [PubMed] [PMC]

124.

Ling D, Marshall GM, Liu PY, Xu N, Nelson CA, Iismaa SE, et al. Enhancing the anticancer effect of the histone deacetylase inhibitor by activating transglutaminase. Eur J Cancer. 2012;48:3278–87. [DOI] [PubMed]

125.

Zhang FY, Du GJ, Zhang L, Zhang CL, Lu WL, Liang W. Naringenin enhances the anti-tumor effect of doxorubicin through selectively inhibiting the activity of multidrug resistance-associated proteins but not P-glycoprotein. Pharm Res. 2009;26:914–25. [DOI] [PubMed]

126.

Qin L, Jin L, Lu L, Lu X, Zhang C, Zhang F, et al. Naringenin reduces lung metastasis in a breast cancer resection model. Protein Cell. 2011;2:507–16. [DOI] [PubMed] [PMC]

127.

Zhang F, Dong W, Zeng W, Zhang L, Zhang C, Qiu Y, et al. Naringenin prevents TGF-β1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation. Breast Cancer Res. 2016;18:38. [DOI] [PubMed] [PMC]

128.

Han KY, Chen PN, Hong MC, Hseu YC, Chen KM, Hsu LS, et al. Naringenin attenuated prostate cancer invasion via reversal of epithelial-to-mesenchymal transition and inhibited uPA activity. Anticancer Res. 2018;38:6753–8. [DOI] [PubMed]

129.

Jang BC, Lim KJ, Paik JH, Cho JW, Baek WK, Suh MH, et al. Tetrandrine-induced apoptosis is mediated by activation of caspases and PKC-delta in U937 cells. Biochem Pharmacol. 2004;67:1819–29. [DOI] [PubMed]

130.

Liu T, Men Q, Wu G, Yu C, Huang Z, Liu X, et al. Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells. Oncotarget. 2015;6:7992–8006. [DOI] [PubMed] [PMC]

131.

Liu T, Zhang Z, Yu C, Zeng C, Xu X, Wu G, et al. Tetrandrine antagonizes acute megakaryoblastic leukaemia growth by forcing autophagy-mediated differentiation. Br J Pharmacol. 2017;174:4308–28. [DOI] [PubMed] [PMC]

132.

Wu G, Liu T, Li H, Li Y, Li D, Li W. c-MYC and reactive oxygen species play roles in tetrandrine-induced leukemia differentiation. Cell Death Dis. 2018;9:473. [DOI] [PubMed] [PMC]

133.

Wu Z, Wang G, Xu S, Li Y, Tian Y, Niu H, et al. Effects of tetrandrine on glioma cell malignant phenotype via inhibition of ADAM17. Tumour Biol. 2014;35:2205–10. [DOI] [PubMed]

134.

Zhang Y, Wen YL, Ma JW, Ye JC, Wang X, Huang JX, et al. Tetrandrine inhibits glioma stem-like cells by repressing β-catenin expression. Int J Oncol. 2017;50:101–10. [DOI] [PubMed]

135.

Ma JW, Zhang Y, Ye JC, Li R, Wen YL, Huang JX, et al. Tetrandrine exerts a radiosensitization effect on human glioma through inhibiting proliferation by attenuating ERK phosphorylation. Biomol Ther (Seoul). 2017;25:186–93. [DOI] [PubMed] [PMC]

136.

Jiang YW, Cheng HY, Kuo CL, Way TD, Lien JC, Chueh FS, et al. Tetrandrine inhibits human brain glioblastoma multiforme GBM 8401 cancer cell migration and invasion in vitro. Environ Toxicol. 2019;34:364–74. [DOI] [PubMed]

137.

Jin Q, Kang C, Soh Y, Sohn NW, Lee J, Cho YH, et al. Tetrandrine cytotoxicity and its dual effect on oxidative stress-induced apoptosis through modulating cellular redox states in Neuro 2a mouse neuroblastoma cells. Life Sci. 2002;71:2053–66. [DOI] [PubMed]

138.

Chen Y, Chen JC, Tseng SH. Effects of tetrandrine plus radiation on neuroblastoma cells. Anticancer Res. 2009;29:3163–71. [PubMed]

139.

Tao LJ, Zhou XD, Shen CC, Liang CZ, Liu B, Tao Y, et al. Tetrandrine induces apoptosis and triggers a caspase cascade in U2-OS and MG-63 cells through the intrinsic and extrinsic pathways. Mol Med Rep. 2014;9:345–9. [DOI] [PubMed]

140.

Tian DD, Zhang RX, Wu N, Yuan W, Luo SH, Chen HQ, et al. Tetrandrine inhibits the proliferation of human osteosarcoma cells by upregulating the PTEN pathway. Oncol Rep. 2017;37:2795–802. [DOI] [PubMed]

141.

Sun X, Xu R, Deng Y, Cheng H, Ma J, Ji J, et al. Effects of tetrandrine on apoptosis and radiosensitivity of nasopharyngeal carcinoma cell line CNE. Acta Biochim Biophys Sin (Shanghai). 2007;39:869–78. [DOI] [PubMed]

142.

Lin YJ, Peng SF, Lin ML, Kuo CL, Lu KW, Liao CL, et al. Tetrandrine induces apoptosis of human nasopharyngeal carcinoma NPC-TW 076 cells through reactive oxygen species accompanied by an endoplasmic reticulum stress signaling pathway. Molecules. 2016;21:1353. [DOI] [PubMed] [PMC]

143.

Cho HS, Chang SH, Chung YS, Shin JY, Park SJ, Lee ES, et al. Synergistic effect of ERK inhibition on tetrandrine-induced apoptosis in A549 human lung carcinoma cells. J Vet Sci. 2009;10:23–8. [DOI] [PubMed] [PMC]

144.

Chen Z, Zhao L, Zhao F, Yang G, Wang JJ. Tetrandrine suppresses lung cancer growth and induces apoptosis, potentially via the VEGF/HIF-1alpha/ICAM-1 signaling pathway. Oncol Lett. 2018;15:7433–7. [DOI] [PubMed] [PMC]

145.

Huang AC, Lien JC, Lin MW, Yang JS, Wu PP, Chang SJ, et al. Tetrandrine induces cell death in SAS human oral cancer cells through caspase activation-dependent apoptosis and LC3-I and LC3-II activation- dependent autophagy. Int J Oncol. 2013;43:485–94. [DOI] [PubMed]

146.

Yu FS, Yu CS, Chen JC, Yang JL, Lu HF, Chang SJ, et al. Tetrandrine induces apoptosis via caspase-8, -9, and -3 and poly (ADP ribose) polymerase dependent pathways and autophagy through beclin-1/LC3-I, II signaling pathways in human oral cancer HSC-3 cells. Environ Toxicol. 2016;31:395–406. [DOI] [PubMed]

147.

Lien JC, Lin MW, Chang SJ, Lai KC, Huang AC, Yu FS, et al. Tetrandrine induces programmed cell death in human oral cancer CAL 27 cells through the reactive oxygen species production and caspase-dependent pathways and associated with beclin-1-induced cell autophagy. Environ Toxicol. 2017;32:329–43. [DOI] [PubMed]

148.

Qin R, Shen H, Cao Y, Fang Y, Li H, Chen Q, et al. Tetrandrine induces mitochondria-mediated apoptosis in human gastric cancer BGC-823 cells. PLoS One. 2013;8:e76486. [DOI] [PubMed] [PMC]

149.

Chaudhary P, Vishwanatha JK. c-Jun NH2-terminal kinase-induced proteasomal degradation of c-FLIPL/S and Bcl2 sensitize prostate cancer cells to Fas- and mitochondria-mediated apoptosis by tetrandrine. Biochem Pharmacol. 2014;91:457–73. [DOI] [PubMed] [PMC]

150.

Liu W, Kou B, Ma ZK, Tang XS, Lv C, Ye M, et al. Tetrandrine suppresses proliferation, induces apoptosis, and inhibits migration and invasion in human prostate cancer cells. Asian J Androl. 2015;17:850–3. [DOI] [PubMed] [PMC]

151.

Kou B, Liu W, He W, Zhang Y, Zheng J, Yan Y, et al. Tetrandrine suppresses metastatic phenotype of prostate cancer cells by regulating Akt/mTOR/MMP-9 signaling pathway. Oncol Rep. 2016;35:2880–6. [DOI] [PubMed]

152.

Li X, Su B, Liu R, Wu D, He D. Tetrandrine induces apoptosis and triggers caspase cascade in human bladder cancer cells. J Surg Res. 2011;166:e45–51. [DOI] [PubMed]

153.

Zhang Y, Liu W, He W, Zhang Y, Deng X, Ma Y, et al. Tetrandrine reverses epithelial-mesenchymal transition in bladder cancer by downregulating Gli-1. Int J Oncol. 2016;48:2035–42. [DOI] [PubMed]

154.

Xu W, Debeb BG, Lacerda L, Li J, Woodward WA. Tetrandrine, a compound common in Chinese traditional medicine, preferentially kills breast cancer tumor initiating cells (TICs) in vitro. Cancers (Basel). 2011;3:2274–85. [DOI] [PubMed] [PMC]

155.

Wong VKW, Zeng W, Chen J, Yao XJ, Leung ELH, Wang QQ, et al. Tetrandrine, an activator of autophagy, induces autophagic cell death via PKC-α inhibition and mTOR-dependent mechanisms. Front Pharmacol. 2017;8:351. [DOI] [PubMed] [PMC]

156.

Wang CH, Yang JM, Guo YB, Shen J, Pei XH. Anticancer activity of tetrandrine by inducing apoptosis in human breast cancer cell line MDA-MB-231 in vivo. Evid Based Complement Alternat Med. 2020;2020:6823520. [DOI] [PubMed] [PMC]

157.

Chen T, Ji B, Chen Y. Tetrandrine triggers apoptosis and cell cycle arrest in human renal cell carcinoma cells. J Nat Med. 2014;68:46–52. [DOI] [PubMed]

158.

Chen S, Liu W, Wang K, Fan Y, Chen J, Ma J, et al. Tetrandrine inhibits migration and invasion of human renal cell carcinoma by regulating Akt/NF-κB/MMP-9 signaling. PLoS One. 2017;12:e0173725. [DOI] [PubMed] [PMC]

159.

Yoo SM, Oh SH, Lee SJ, Lee BW, Ko WG, Moon CK, et al. Inhibition of proliferation and induction of apoptosis by tetrandrine in HepG2 cells. J Ethnopharmacol. 2002;81:225–9. [DOI] [PubMed]

160.

Oh SH, Lee BH. Induction of apoptosis in human hepatoblastoma cells by tetrandrine via caspase- dependent Bid cleavage and cytochrome c release. Biochem Pharmacol. 2003;66:725–31. [DOI] [PubMed]

161.

Ng LT, Chiang LC, Lin YT, Lin CC. Antiproliferative and apoptotic effects of tetrandrine on different human hepatoma cell lines. Am J Chin Med. 2006;34:125–35. [DOI] [PubMed]

162.

Liu C, Gong K, Mao X, Li W. Tetrandrine induces apoptosis by activating reactive oxygen species and repressing Akt activity in human hepatocellular carcinoma. Int J Cancer. 2011;129:1519–31. [DOI] [PubMed]

163.

Gong K, Chen C, Zhan Y, Chen Y, Huang Z, Li W. Autophagy-related gene 7 (ATG7) and reactive oxygen species/extracellular signal-regulated kinase regulate tetrandrine-induced autophagy in human hepatocellular carcinoma. J Biol Chem. 2012;287:35576–88. [DOI] [PubMed] [PMC]

164.

Yu VWL, Ho WS. Tetrandrine inhibits hepatocellular carcinoma cell growth through the caspase pathway and G2/M phase. Oncol Rep. 2013;29:2205–10. [DOI] [PubMed]

165.

Huang T, Xu S, Deo R, Ma A, Li H, Ma K, et al. Targeting the Ca²⁺/Calmodulin-dependent protein kinase II by Tetrandrine in human liver cancer cells. Biochem Biophys Res Commun. 2019;508:1227–32. [DOI] [PubMed]

166.

Chang KH, Liao HF, Chang HH, Chen YY, Yu MC, Chou CJ, et al. Inhibitory effect of tetrandrine on pulmonary metastases in CT26 colorectal adenocarcinoma-bearing BALB/c mice. Am J Chin Med. 2004;32:863–72. [DOI] [PubMed]

167.

Chen XL, Ren KH, He HW, Shao RG. Involvement of PI3K/AKT/GSK3beta pathway in tetrandrine-induced G1 arrest and apoptosis. Cancer Biol Ther. 2008;7:1073–8. [DOI] [PubMed]

168.

Wu JM, Chen Y, Chen JC, Lin TY, Tseng SH. Tetrandrine induces apoptosis and growth suppression of colon cancer cells in mice. Cancer Lett. 2010;287:187–95. [DOI] [PubMed]

169.

He BC, Gao JL, Zhang BQ, Luo Q, Shi Q, Kim SH, et al. Tetrandrine inhibits Wnt/β-catenin signaling and suppresses tumor growth of human colorectal cancer. Mol Pharmacol. 2011;79:211–9. [DOI] [PubMed] [PMC]

170.

Wu K, Zhou M, Wu QX, Yuan SX, Wang DX, Jin JL, et al. The role of IGFBP-5 in mediating the anti-proliferation effect of tetrandrine in human colon cancer cells. Int J Oncol. 2015;46:1205–13. [DOI] [PubMed]

171.

Tsai SC, Wu WC, Yang JS. Tetrandrine inhibits epithelial-mesenchymal transition in IL-6-induced HCT116 human colorectal cancer cells. Onco Targets Ther. 2021;14:4523–36. [DOI] [PubMed] [PMC]

172.

Zhang H, Xie B, Zhang Z, Sheng X, Zhang S. Tetrandrine suppresses cervical cancer growth by inducing apoptosis in vitro and in vivo. Drug Des Devel Ther. 2018;13:119–27. [DOI] [PubMed] [PMC]

173.

Zhu R, Liu T, Tan Z, Wu X, Li M, Jiang L, et al. Tetrandrine induces apoptosis in gallbladder carcinoma in vitro. Int J Clin Pharmacol Ther. 2014;52:900–5. [DOI] [PubMed]

174.

Singh K, Dong Q, TimiriShanmugam PS, Koul S, Koul HK. Tetrandrine inhibits deregulated cell cycle in pancreatic cancer cells: differential regulation of p21^Cip1/Waf1, p27^Kip1 and cyclin D1. Cancer Lett. 2018;425:164–73. [DOI] [PubMed]

175.

Zhang Y, Wang C, Wang H, Wang K, Du Y, Zhang J. Combination of tetrandrine with cisplatin enhances cytotoxicity through growth suppression and apoptosis in ovarian cancer in vitro and in vivo. Cancer Lett. 2011;304:21–32. [DOI] [PubMed]

176.

Favia A, Pafumi I, Desideri M, Padula F, Montesano C, Passeri D, et al. NAADP-dependent Ca(2+) signaling controls melanoma progression, metastatic dissemination and neoangiogenesis. Sci Rep.2016;6:18925. [DOI] [PubMed] [PMC]

177.

Faris P, Pellavio G, Ferulli F, Di Nezza F, Shekha M, Lim D, et al. Nicotinic acid adenine dinucleotide phosphate (NAADP) induces intracellular Ca²⁺ release through the two-pore channel TPC1 in metastatic colorectal cancer cells. Cancers (Basel). 2019;11:542. [DOI] [PubMed] [PMC]

178.

Correale P, Tagliaferri P, Celio L, Genua G, Montagnani S, Bianco AR. Verapamil upregulates sensitivity of human colon and breast cancer cells to LAK-cytotoxicity in vitro. Eur J Cancer. 1991;27:1393–5. [DOI] [PubMed]

179.

Bruserud O, Pawelec G. Effects of dipyridamole and R-verapamil on in vitro proliferation of blast cells from patients with acute myelogenous leukaemia. Leuk Res. 1993;17:507–13. [DOI] [PubMed]

180.

Bruserud O. Effect of dipyridamole, theophyllamine and verapamil on spontaneous in vitro proliferation of myelogenous leukaemia cells. Acta Oncol. 1992;31:53–8. [DOI] [PubMed]

181.

Yoon H, Kim TW, Shin SY, Park MJ, Yong Y, Kim DW, et al. Design, synthesis and inhibitory activities of naringenin derivatives on human colon cancer cells. Bioorg Med Chem Lett. 2013;23:232–8. [DOI] [PubMed]

182.

Rebello CJ, Beyl RA, Lertora JJL, Greenway FL, Ravussin E, Ribnicky DM, et al. Safety and pharmacokinetics of naringenin: a randomized, controlled, single-ascending-dose clinical trial. Diabetes Obes Metab. 2020;22:91–8. [DOI] [PubMed] [PMC]

183.

Tundis R, Loizzo MR, Menichini F, Bonesi M, Colica C, Menichini F. In vitro cytotoxic activity of extracts and isolated constituents of Salvia leriifolia Benth. Against a panel of human cancer cell lines. Chem Biodivers. 2011;8:1152–62. [DOI] [PubMed]

184.

Schutz R, Muller M, Geisslinger F, Vollmar A, Bartel K, Bracher F. Synthesis, biological evaluation and toxicity of novel tetrandrine analogues. Eur J Med Chem. 2020;207:112810. [DOI] [PubMed] [PMC]

185.

Liu T, Liu X, Li W. Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy. Oncotarget. 2016;7:40800–15. [DOI] [PubMed] [PMC]

186.

Chi M, Evans H, Gilchrist J, Mayhew J, Hoffman A, Pearsall EA, et al. Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells. Sci Rep. 2016;6:33132. [DOI] [PubMed] [PMC]

187.

Hoffman A, Carpenter H, Kahl R, Watt LF, Dickson PW, Rostas JA, et al. Dephosphorylation of CaMKII at T253 controls the metaphase-anaphase transition. Cell Signal. 2014;26:748–56. [DOI] [PubMed]

188.

Wang J, Guo M, Ma R, Wu M, Zhang Y. Tetrandrine alleviates cerebral ischemia/reperfusion injury by suppressing NLRP3 inflammasome activation via Sirt-1. PeerJ. 2020;8:e9042. [DOI] [PubMed] [PMC]

189.

Song MY, Wang JX, Sun YL, Han ZF, Zhou YT, Liu Y, et al. Tetrandrine alleviates silicosis by inhibiting canonical and non-canonical NLRP3 inflammasome activation in lung macrophages. Acta Pharmacol Sin. 2021;[Epub ahead of print]. [DOI] [PubMed]

190.

Wang J, Yao Z, Lai X, Bao H, Li Y, Li S, et al. Tetrandrine sensitizes nasopharyngeal carcinoma cells to irradiation by inducing autophagy and inhibiting MEK/ERK pathway. Cancer Med. 2020;9:7268–78. [DOI] [PubMed] [PMC]

191.

Xu XH, Gan YC, Xu GB, Chen T, Zhou H, Tang JF, et al. Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis. J Zhejiang Univ Sci B. 2012;13:867–74. [DOI] [PubMed] [PMC]

192.

Zhu X, Sui M, Fan W. In vitro and in vivo characterizations of tetrandrine on the reversal of P-glycoprotein- mediated drug resistance to paclitaxel. Anticancer Res. 2005;25:1953–62. [PubMed]

193.

Jin J, Wang FP, Wei H, Liu G. Reversal of multidrug resistance of cancer through inhibition of P-glycoprotein by 5-bromotetrandrine. Cancer Chemother Pharmacol. 2005;55:179–88. [DOI] [PubMed]

194.

Liu ZL, Hirano T, Tanaka S, Onda K, Oka K. Persistent reversal of P-glycoprotein-mediated daunorubicin resistance by tetrandrine in multidrug-resistant human T lymphoblastoid leukemia MOLT-4 cells. J Pharm Pharmacol. 2003;55:1531–7. [DOI] [PubMed]

195.

Wan J, Liu T, Mei L, Li J, Gong K, Yu C, et al. Synergistic antitumour activity of sorafenib in combination with tetrandrine is mediated by reactive oxygen species (ROS)/Akt signaling. Br J Cancer. 2013;109:342–50. [DOI] [PubMed] [PMC]

196.

Chen Y, Li P, Yang S, Tong N, Zhang J, Zhao X. Tetrandrine enhances the anticancer effects of arsenic trioxide in vitro. Int J Clin Pharmacol Ther. 2014;52:416–24. [DOI] [PubMed]

197.

Mei L, Chen Y, Wang Z, Wang J, Wan J, Yu C, et al. Synergistic anti-tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21. Br J Pharmacol. 2015;172:2232–45. [DOI] [PubMed] [PMC]

198.

Yu M, Liu T, Chen Y, Li Y, Li W. Combination therapy with protein kinase inhibitor H89 and tetrandrine elicits enhanced synergistic antitumor efficacy. J Exp Clin Cancer Res. 2018;37:114. [DOI] [PubMed] [PMC]

199.

Xu WL, Shen HL, Ao ZF, Chen BA, Xia W, Gao F, et al. Combination of tetrandrine as a potential-reversing agent with daunorubicin, etoposide and cytarabine for the treatment of refractory and relapsed acute myelogenous leukemia. Leuk Res. 2006;30:407–13. [DOI] [PubMed]

200.

Liu W, Zhang J, Ying C, Wang Q, Yan C, Jingyue Y, et al. Tetrandrine combined with gemcitabine and cisplatin for patients with advanced non-small cell lung cancer improve efficacy. Int J Biomed Sci. 2012;8:28–35. [PubMed] [PMC]

201.

Jin H, Li L, Zhong D, Liu J, Chen X, Zheng J. Pulmonary toxicity and metabolic activation of tetrandrine in CD-1 mice. Chem Res Toxicol. 2011;24:2142–52. [DOI] [PubMed]

202.

Tian Y, Shen S, Jiang Y, Shen Q, Zeng S, Zheng J. CYP3A5 mediates bioactivation and cytotoxicity of tetrandrine. Arch Toxicol. 2016;90:1737–48. [DOI] [PubMed]

203.

Shi JP, Li SX, Ma ZL, Gao AL, Song YJ, Zhang H. Acute and sub-chronic toxicity of tetrandrine in intravenously exposed female BALB/c mice. Chin J Integr Med. 2016;22:925–31. [DOI] [PubMed]

204.

Zhang YX, Liu XM, Wang J, Li J, Liu Y, Zhang H, et al. Inhibition of AKT/FoxO3a signaling induced PUMA expression in response to p53-independent cytotoxic effects of H1: a derivative of tetrandrine. Cancer Biol Ther. 2015;16:965–75. [DOI] [PubMed] [PMC]

205.

Wei N, Sun H, Wang F, Liu G. H1, a novel derivative of tetrandrine reverse P-glycoprotein-mediated multidrug resistance by inhibiting transport function and expression of P-glycoprotein. Cancer Chemother Pharmacol. 2011;67:1017–25. [DOI] [PubMed]

206.

Lin Y, Wang Y, Liu X, Yan J, Su L, Liu X. A novel derivative of tetrandrine (H1) induces endoplasmic reticulum stress-mediated apoptosis and prosurvival autophagy in human non-small cell lung cancer cells. Tumour Biol. 2016;37:10403–13. [DOI] [PubMed]

207.

Naylor E, Arredouani A, Vasudevan SR, Lewis AM, Parkesh R, Mizote A, et al. Identification of a chemical probe for NAADP by virtual screening. Nat Chem Biol. 2009;5:220–6. [DOI] [PubMed] [PMC]

208.

Jin X, Zhang Y, Alharbi A, Hanbashi A, Alhoshani A, Parrington J. Targeting two-pore channels: current progress and future challenges. Trends Pharmacol Sci. 2020;41:582–94. [DOI] [PubMed] [PMC]

209.

Simpson WG. The calcium channel blocker verapamil and cancer chemotherapy. Cell Calcium. 1985;6:449–67. [DOI] [PubMed]

210.

Genazzani AA, Mezna M, Dickey DM, Michelangeli F, Walseth TF, Galione A. Pharmacological properties of the Ca²⁺-release mechanism sensitive to NAADP in the sea urchin egg. Br J Pharmacol. 1997;121:1489–95. [DOI] [PubMed] [PMC]

211.

Pahor M, Furberg CD. Is the use of some calcium antagonists linked to cancer? Evidence from recent observational studies. Drugs Aging. 1998;13:99–108. [DOI] [PubMed]

212.

Solary E, Bidan JM, Calvo F, Chauffert B, Caillot D, Mugneret F, et al. P-glycoprotein expression and in vitro reversion of doxorubicin resistance by verapamil in clinical specimens from acute leukaemia and myeloma. Leukemia. 1991;5:592–7. [PubMed]

213.

Ledwitch KV, Gibbs ME, Barnes RW, Roberts AG. Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein. Biochem Pharmacol. 2016;118:96–108. [DOI] [PubMed] [PMC]

214.

Muller C, Bailly JD, Goubin F, Laredo J, Jaffrezou JP, Bordier C, et al. Verapamil decreases P-glycoprotein expression in multidrug-resistant human leukemic cell lines. Int J Cancer. 1994;56:749–54. [DOI] [PubMed]

215.

McCarthy M, Auda G, Agrawal S, Taylor A, Backstrom Z, Mondal D, et al. In vivo anticancer synergy mechanism of doxorubicin and verapamil combination treatment is impaired in BALB/c mice with metastatic breast cancer. Exp Mol Pathol. 2014;97:6–15. [DOI] [PubMed]

216.

Shiozaki A, Katsurahara K, Kudou M, Shimizu H, Kosuga T, Ito H, et al. Amlodipine and verapamil, voltage-gated Ca²⁺ channel inhibitors, suppressed the growth of gastric cancer stem cells. Ann Surg Oncol. 2021;28:5400–11. [DOI] [PubMed]

217.

Maruyama Y, Murohashi I, Nara N, Aoki N. Effects of verapamil on the cellular accumulation of daunorubicin in blast cells and on the chemosensitivity of leukaemic blast progenitors in acute myelogenous leukaemia. Br J Haematol. 1989;72:357–62. [DOI] [PubMed]

218.

Tsuruo T, Iida H, Yamashiro M, Tsukagoshi S, Sakurai Y. Enhancement of vincristine- and adriamycin-induced cytotoxicity by verapamil in P388 leukemia and its sublines resistant to vincristine and adriamycin. Biochem Pharmacol. 1982;31:3138–40. [DOI] [PubMed]

219.

Li P, Zhong D, Gong PY. Synergistic effect of paclitaxel and verapamil to overcome multi-drug resistance in breast cancer cells. Biochem Biophys Res Commun. 2019;516:183–8. [DOI] [PubMed]

220.

Wang X, Wang Z, Wang K, Gao M, Zhang H, Xu X. Metabolomics analysis of multidrug resistance in colorectal cancer cell and multidrug resistance reversal effect of verapamil. Biomed Chromatogr. 2021;35:e4976. [DOI] [PubMed]

221.

Schuldes H, Dolderer JH, Zimmer G, Knobloch J, Bickeboller R, Jonas D, et al. Reversal of multidrug resistance and increase in plasma membrane fluidity in CHO cells with R-verapamil and bile salts. Eur J Cancer. 2001;37:660–7. [DOI] [PubMed]

222.

Candussio L, Decorti G, Crivellato E, Granzotto M, Rosati A, Giraldi T, et al. Toxicologic and pharmacokinetic study of low doses of verapamil combined with doxorubicin. Life Sci. 2002;71:3109–19. [DOI] [PubMed]

223.

Ries F, Dicato M. Treatment of advanced and refractory breast cancer with doxorubicin, vincristine and continuous infusion of verapamil. A phase I–II clinical trial. Med Oncol Tumor Pharmacother. 1991;8:39–43. [DOI] [PubMed]

224.

Pingsheng F, Tengyue Z, Qiang H, Qiang W, Xin S, Liting Q. Basic and clinical research on the therapeutic effect of intervention in primary liver cancer by targeted intra-arterial verapamil infusion. Cell Biochem Biophys. 2012;62:59–67. [DOI] [PubMed]

225.

Huang J, Zhang T, Ma K, Fan P, Liu Y, Weng C, et al. Clinical evaluation of targeted arterial perfusion of verapamil and chemotherapeutic drugs in interventional therapy of advanced lung cancer. Cancer Chemother Pharmacol. 2013;72:889–96. [DOI] [PubMed] [PMC]

226.

Fan GF, Pan JJ, Fan PS, Zhang TY, Liu YB, Huang J, et al. The clinical observation of verapamil in combination with interventional chemotherapy in advanced gastric cancer. Eur Rev Med Pharmacol Sci. 2018;22:5508–18. [DOI] [PubMed]