Table Info

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]

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

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