Induction of apoptosis and antitumor effects of a small molecule inhibitor of Bcl-2 and Bcl-xl, gossypol acetate, in multiple myeloma in vitro and in vivo

Abstract

Gossypol is a naturally occurring polyphenolic compound extracted from cotton plants. Recent studies revealed that gossypol is a non-peptidic small molecule inhibitor of Bcl-2/Bcl-xl. The aim of the present study was to investigate the induction of apoptosis and antitumor effects of gossypol acetate in multiple myeloma and the possible mechanism(s) of action. Our results showed that gossypol acetate resulted in a dose- and time-dependent inhibition of multiple myeloma cell proliferation, with an IC50 value to both U266 and Wus1 cells at 2.4, 2.2 µM at 48 h after treatment. Gossypol acetate effectively induced the apoptosis of multiple myeloma cells as demonstrated by typical morphological changes, DNA ladder formation and increase in the percentage of cells in subdiploid peak. Furthermore, colorimetric assays showed activation of both caspase-3 and caspase-9. Bcl-2 and Bcl-xl expression was decreased by 86.5±1.2% and 35.9±3.6%, respectively, after treatment with gossypol acetate at 25 µmol/l for 24 h. Preliminary studies in vivo showed that a growth inhibition (T/C) of 30.9% (gossypol acetate 40 mg/kg) was obtained in Balb/C mice bearing Wus1 cells. In addition, there was no body weight loss for the treated group in comparison with the vehicle mice. Our results demonstrated that the potent inhibitor of Bcl-2 and Bcl-xl gossypol acetate had significant antiproliferative and antiapoptotic effects on multiple myeloma cells in vitro and in vivo. Gossypol acetate may represent a promising new anticancer agent with a novel molecular mechanism and warrants further investigation as a single agent, or in combination with other chemotherapeutics, for human multiple myeloma with Bcl-2 overexpression.

Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway

“…During the preparation of this report, we noticed that another group reported apoptosis inducing effect of Gos in MM cells (43). In contrast to our findings, they showed that Gos decreased protein levels of Bcl-2 and Bcl-X L by flow cytometry, although they did not examine the phosphorylation status of Bcl-2.…”

Pharmacologic inhibition of lactate production prevents myofibroblast differentiation

“…In cancer cells it can inhibit cell cycle progression and promote apoptosis (6,12,19,21,31). Although we have focused on inhibition of LDH activity as a pathway to blocking TGF-␤ activity, these other activities could potentially be important in treating fibrosis.…”

“…Gossypol has also been shown to promote cellular apoptosis and interfere with the regulation of the cell cycle and/or cellular proliferation (20,21,31,34). Many of the properties of gossypol appear to be dose and cell type specific.…”

Mangiferin enhances the sensitivity of human multiple myeloma cells to anticancer drugs through suppression of the nuclear factor κB pathway

“…MM cells express high levels of XIAP regulated by the NF-κB pathway (31). The Bcl-2 family member Bcl-xL is an antiapoptotic protein; Bcl-xL overexpression has been reported in MM cell lines (32,33). These results suggest that the combination of mangiferin and an anticancer drug induces apoptosis by increasing the expression of p53 and Noxa and decreasing that of XIAP, survivin, and Bcl-xL proteins via inhibition of the NF-κB pathway.…”