Synergistic antitumoral activity and induction of apoptosis by novel pan Bcl-2 proteins inhibitor apogossypolone with adriamycin in human hepatocellular carcinoma

Abstract

Aim: To investigate the in vitro and in vivo activities and related mechanism of apogossypolone (ApoG2) alone or in combination with adriamycin (ADM) against human hepatocellular carcinoma (HCC). Methods: The IC 50 of ApoG2 in vitro was tested by WST assay, and the synergistic effect was analyzed using the CalcuSyn method. Cell apoptosis was determined using 4',6-diamidino-2-phenylindole staining and flow cytometric analysis. Western blotting was used to determine the expression of apoptosis-related proteins. In vivo activity was evaluated in the xenograft model in nude mice, and apoptosis in tumor tissues was determined by terminal deoxynucleotidyl transferase-mediated digoxigenindUTP nick-end labeling (TUNEL) assay. Results: The IC 50 of ApoG2 in HCC cells was 17.28-30.63 μmol/L. When ApoG2 was combined with ADM, increased cytotoxicity and apoptosis were observed in SMMC-7721 cells compared to treatment with ApoG2 alone. The Western blotting results indicated that the ApoG2 induced apoptosis in SMMC-7721 cells by downregulating anti-apoptotic proteins Bcl-2, Mcl-1, and Bcl-X L , up-regulating pro-apoptotic protein Noxa, and promoting the activities of caspases-9 and -3. The tumor growth of xenograft SMMC-7721 was inhibited in nude mice when ApoG2 was administered orally without causing damage to the normal tissues. The in vivo study also indicated an increasing anti-tumoral effect when ApoG2 at 100 or 200 mg/kg dosages were used together with ADM at 5.5 mg/kg, with relative tumor proliferation rate (T/C) values of 0.456 and 0.323, respectively. Apoptosis induced in vivo by ApoG2 alone or combined with ADM was confirmed by TUNEL assay in tumor tissues. Conclusion: ApoG2 is a potential non-toxic target agent that induces apoptosis by upregulating Noxa, while inhibiting anti-apoptotic proteins and promoting the effect of chemotherapy agent ADM in HCC.

Mulberry-like dual-drug complicated nanocarriers assembled with apogossypolone amphiphilic starch micelles and doxorubicin hyaluronic acid nanoparticles for tumor combination and targeted therapy

“…As one of the broad-spectrum anti-tumor drugs, doxorubicin (DOX) has been widely used for tumor combination therapy with other anti-tumor drugs [21,22]. Mi et al found that ApoG2 had a significant in vivo anti-tumor effect in combination with DOX and promoted the therapy effect of chemotherapy agent DOX in human hepatocellular carcinoma [23]. Therefore, combination therapy with ApoG2 and DOX is a potential method to improve the individual therapy effect of ApoG2 and DOX alone.…”

Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation

“…Despite recent improvements in surveillance programs and diagnostic tools allowing identification of small suspicious nodules, only 30% to 40% of patients with HCC are eligible for curative treatments [4] . In well-selected patients, resection and liver transplantation provide 5-year survival rates of 70%, whereas local ablation with radio frequency results in a 5-year survival rate of 50% [5] . These treatments change the natural course of the disease.…”

Bcl-2 Family Proteins as Therapeutic Targets

“…More recent studies have greatly expanded the range of cancer cell lines sensitive to ApoG2. It was found to be active against hepatocellular cancer cell lines with IC 50 values ranging from 17 to 31 μM [124]. ApoG2 also enhanced the activity of adryamicin on these cell lines.…”