Targeted constitutive activation of signal transducer and activator of transcription 3 in human hepatocellular carcinoma cells by cucurbitacin B

Abstract

Our results suggest that cucurbitacin B may have a therapeutic value in suppressing the growth of human hepatocellular carcinoma. The mechanism may be attributable to the suppression of STAT3 phosphorylation.

Terpenoids as potential chemopreventive and therapeutic agents in liver cancer

“…Cucurbitacin B, one of the most abundant forms of cucurbitacins, was found to effectively decrease the viability of HepG2 cells through apoptosis with a simultaneous decrease in the levels of the pro-apoptotic protein Bcl-2. Suppression of transcription factor signal transducer and activator of transcription-3 (STAT3) phosphorylation was associated with the cell killing effect of this natural compound [83] . Chan et al [84] were successful in achieving similar growth inhibitory effects of cucurbitacin B in Bel-7402 cells.…”

“…Zhang et al [83] showed the decrease in tumor volume along with tumor growth inhibition exerted by cucurbitacin B in mice xenografted with HepG2 cells, whereas Chan et al [84] demonstrated the inhibitory activity of cucurbitacin B on the growth of xenografted BEL-7402 tumor. Nevertheless, the in vivo mechanisms of such antitumor effects of cucurbitacin B were not studied.…”

“…Suppressed the formation of BHC-induced nodules in Swiss male albino mice ↑GSH; ↑GR; ↑GPX; ↑SOD; ↑ CAT; ↓GGT; ↓GST 5-10 mg/kg per day; 1-8 mo po Trivedi et al [137] Reversed histomorphological and ultrastructural changes during BHC-induced hepatocarcinogenesis male Swiss mice [83] Inhibited tumor growth in BEL-7402 xenografted mice model 0.1-3 mg/kg; twice per day for 26 d po Chan et al [84] Escin Demonstrated inhibitory effects on tumor growth in H22 tumor-bearing female Kunming mice 1.4-2.8 mg/kg; 7 d ip Zhou et al [88] Ginseng extract Inhibited AFB1-initiated and FB-promoted hepatocarcinogenesis in female SD rats ↓ALT; ↓AST; ↑albumin; ↓TG; ↓cholesterol; ↓LDL; ↑HDL; ↓AFP, ↓CEA, ↓MDA, ↑TAC; ↓fibrosis 150 mg/kg; 1-12 wk po Abdel-Wahhab et al [145] Glycyrrhizin Decreased the incidence of nodules and HCC induced by DENA in BALB/c mice ↑albumin; ↑AST 2 mg/animal; 3 d/wk for 12-32 wk im Shiota et al [146] Reduced the size, volume and number of preneoplastic liver lesions initiated by DENA and promoted with 2-AAF in male SD rats 0.1% 25 mg/kg; 1 wk po Wan et al [147] EC-2, EC-4 Failed to show modifying effects against DENAinduced hepato-carcinogenesis in male F-344 rats 1 mg/kg; 5 times a week for 2-8 wk po Karim et al [148] Squalene Failed to exhibit chemoprevention against DENA-initiated and 2-AAF-promoted hepatocarcinogenesis in male Wistar rats ↑ plasma cholesterol 1-1.5 g/kg; 8 wk po Scolastici et al [149] Ursolic acid Inhibited the growth of H22 hepatoma implanted in male CD-1 mice [111] Tetraterpenoids α-Carotene Decreased the number of hepatomas during spontaneous hepatocarcinogenesis in male C3H/He mice 0.005%-0.05%; 40 wk dw Murakoshi et al [151] Reduced the number of liver tumors in multiorgan carcinogenesis in male and female B6C3F1 mice 0.4 mg/mouse; three times a week for 24 wk po Tsuda et al [152] β-Carotene Failed to have an effect on the number and size of preneoplastic liver foci induced by DENA/2-AAF/PB in male Wistar rats 300 mg/kg diet or 10 mg/kg bw (3 times/wk); 3 wk…”

“…1-50 μg/mL Eichenmüller et al [80] Failed to induce apoptosis against HepG2 cells ↑survivin; ↑Bcl-2 0.1-50 μg/mL Eichenmüller et al [80] Cucurbitacin B Decreased the viability of HepG2 cells ↑apoptosis; ↓Bcl-2; ↓pSTAT3 10 nmol/L-10 μmol/L Zhang et al [83] Exhibited growth inhibitory effects on Bel-7402 cells ↑apoptosis; ⊥S; ↓cyclin D1; ↓cdc2; ↓c-Raf; ↑ERK 1/2 0.01-1000 μmol/L Chan et al [84] Cucurbitacin D Suppressed the growth of Hep3b cells ↑apoptosis; ↑caspase-3; ↑pJNK 0-10 μmol/L Takahashi et al [85] Cucurbitacin D, I Displayed cytotoxicity against Bel-7402 cells…”

In vitroandin vivoanticancer properties of cucurbitacin isolated fromCayaponia racemosa

“…Jayaprakasam and co-workers demonstrated the cytotoxic properties of cucurbitacins B, D, E and I, isolated from the fruits of Cucurbita andreana, against colon, breast, lung and central nervous system cancer cell lines (Jayaprakasam et al, 2003). Among this class of compounds, cucurbitacin B is the most studied, and while several studies demonstrated its efficacy in different models of cancer, including in vivo tumor xenografts (Liu et al, 2008;Wakimoto et al, 2008;Zhang et al, 2009;Chan et al, 2010), there is disagreement regarding the mechanisms underlying its anticancer activity. Suppression of the oncogene STAT 3 (signal transducer and activator of transcription 3) appears to be related to tumor inhibition (Zhang et al, 2004;Chan et al, 2010b), which does not exclude alternative mechanisms (Yasuda et al, 2010).…”