From:  Targeting the two-pore channel 2 in cancer progression and metastasis

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

CancerCell line(s)EffectsMechanismRef
GrowthCell deathMigration & invasionGrowth in vivo
Naringenin
GliomaC6---↓ROS, cyclin D1, NFκB, CDK4[118]
C6---↓PI3K, PKB[119]
U-118MG-↑---[108]
GBM8401None↑↓-MMP[109]
MelanomaB16F10↓↑-↓ (lung mets)Transglutaminase[110]
B16F10↓↑---[111]
B16F10, SK- MEL-28↓↑↓-ERK1/2, JNK, MAPK, PARP, caspase[112]
B16F10---↓TGFβ-Smad-MMP2[120]
Breast cancerMDA-MB-435↓--↓ (delayed tumor growth; DMBA rat)-[91]
4T1None--↓ (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 cancerAzoxymethane 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, T84NoneNone--MAPK[122]
Hepatic carcinomaHepG2↓↑--P53, caspase[103]
NDEA-induced rat model---↓PCNA, Bcl-2, NFκB, VEGF, MMP[116]
NDEA-induced rat model---↓Antioxidant[117]
Prostate cancerPC3, LnCaP↓↑↓-ROS, mitochondria[104]
PC3--↓-EMT, uPA activity[128]
Mat-LyLu↓-↓-SCN9A[105]
Pancreatic cancerASPC-1, PANC-1-↑↓-EMT[106]
SNU-213-↑--ROS[107]
Lung cancerNRG mice model---↓CYP1A1, NFκB, PCNA[121]
A549↓-↓-MMP-2/9, Akt[113]
A549↓↑↓-Caspase, MMP[114]
LLC---↓TGFβ-Smad-MMP2[120]
Tetrandrine
AMLU937↓↑--Caspase, JNK, PKC-δ[129]
NB4↓--↓ROS, Notch-1[130]
K562, 6133 MPLW515L↓↑--P21, p27, ROS, Notch-1 signaling[131]
HL60, K562, U937, THP-1↓↑-↓ROS, c-myc[132]
GliomaRT-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]
NeuroblastomaNeuro2a↓↑--ROS[137]
SHSY5Y-↑---[138]
OsteosarcomaU-20S, MG-63-↑--Apaf-1, Bid, Bax, Bcl-2[139]
143B↓↑-↓PTEN, PCNA[140]
Nasopharyngeal carcinomaCNE-↑--Bax/Bcl-2[141]
NPC-TW076↓↑--Endoplasmic reticulum stress[142]
Lung cancerA549↓↑--Akt, ERK[143]
A549↓↑--VEGF/HIF-1/ICAM-1[144]
Oral cancerSAS-↑--PARP, caspase[145]
HSC-3-↑--PARP, caspase, beclin-1/LC3-1/II signaling[146]
CAL27-↑--ROS, caspase, Beclin-1 signaling[147]
Gastric cancerBGC-823-↑--Caspase/mitochondria- mediated[148]
HGC-27-↑--PARP, caspase, Beclin-1/LC3-II/p62, Akt/mTOR[67]
Prostate cancerDU145, PC3↓↑--ROS, JNK1/2[149]
DU145, PC3↓↑↓-PARP, PI3K/Akt[150]
DU145, PC3--↓-Akt/mTOR/MMP-9 signaling[151]
Bladder cancer5637, T24-↑--Caspase/mitochondria- mediated[152]
5637, T24--↓-Inducing MET through downregulation of Gli-1[153]
Breast cancerSUM-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 carcinoma786-O, 769-P, ACHN↓↑--Caspase, p21 and p27[157]
786-O, 769-P--↓-MMP-9, PI3K/Akt, NFκB[158]
Hepatic carcinomaHepG2↓↑--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 cancerCT-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 cancerSiHa↓↑↓↓Caspase, MMP-2, MMP-9[172]
Gallbladder cancerSGC-996↓↑--Caspase, PARP, mitochondria[173]
Pancreatic cancerPaCa↓--↓P21, p27, cyclin D[174]
Ovarian cancerOVCAR-3, A2780↓↑-↓Wnt, E-cadherin, cyclin D, c-myc[175]
Ned-19
Bladder cancerT24--↓-Endocytic recycling[51]
Hepatic carcinomaHuh7--↓-Endocytic recycling[51]
Breast cancer4T1--↓↓Endocytic recycling[51]
MelanomaB16↓↑↓↓VEGF[176]
Colorectal cancerPatient samples↓---ERK, Akt[177]
Verapamil
Breast cancerZR-751A↑----[178]
Colorectal cancerLoVo↑----[178]
AMLPatient samples↓----[179]
Patient samples↓----[180]
CMLPatient samplesNone----[180]
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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