Combination Therapy with Gossypol Reveals Synergism against Gemcitabine Resistance in Cancer Cells with High BCL-2 Expression

Abstract

Although gemcitabine is highly active in several cancer types, intrinsic and acquired drug resistance remains a major challenge. Overexpression of Bcl-2 has been associated with gemcitabine resistance. The aim of this study is to determine whether gossypol can overcome gemcitabine resistance in cell lines with high level of Bcl-2 expression in combination drug therapy. Our study demonstrated that in 10 cell lines derived from different cancers, high Bcl-2 baseline expression was observed in cell lines that were resistant to gemcitabine (GEM-R). Furthermore, synergistic effect of combination therapy was observed in gemcitabine-resistant (GEM-R) cell lines with high Bcl-2 expression, but not in a gemcitabine-sensitive (GEM-S) cell lines regardless of Bcl-2 expression. Gossypol treatment resulted in the decrease of anti-apoptotic genes such as Bcl-2 and Bcl-xl and an upregulation of the pro-apoptotic gene, Noxa. Furthermore, the addition of gossypol to gemcitabine resulted in lower expressions of anti-apoptotic genes compared to gemcitabine alone. Gene expression profiling in GEM-R and GEM-S cell lines suggest that anti-apoptotic genes such as pAkt and PI3KR2 may play important role in gemcitabine resistance, while pro-apoptotic Bcl-2 related genes (Bad, Caspase-6 and Calpain-1) may regulate synergistic interaction in combination therapy.

Gossypol sensitizes the antitumor activity of 5-FU through down-regulation of thymidylate synthase in human colon carcinoma cells

“…Gossypol can overcome gemcitabine resistance in cell lines with a high level of Bcl-2 expression and sensitize cancer cells to TRAIL or docetaxel in combination drug therapy [20][21][22]. Currently, gossypol is being evaluated in phase I and II clinical trials for use as a single agent or in combination with other anti-tumor agents in a variety of hematologic, lymphoid, and solid tumor malignancies [23,24].…”

Identification of glucuronidation and biliary excretion as the main mechanisms for gossypol clearance:in vivoandin vitroevidence

“…The mechanisms of anticancer action include decrease of anti-apoptotic genes (e.g. Bcl-2, Bcl-xl, and Mcl-1), induction of oxidative stress, and downregulation of the co-activators SRC-1 and SRC-3 (Lian et al, 2012;Wang et al, 2011Wang et al, , 2013Wong et al, 2012).…”

Small-molecule BH3 mimetic and pan-Bcl-2 inhibitor AT-101 enhances the antitumor efficacy of cisplatin through inhibition of APE1 repair and redox activity in non-small-cell lung cancer

“…Gossypol can activate the intrinsic apoptotic pathway by increasing the generation of reactive oxygen species,68 activating p53,69 and suppressing NF-κB activity 70,71. Gossypol can upregulate the expression of proapoptotic BH3-only proteins and induce a conformational change in Bcl-2, which renders it proapoptotic 72,73. As a potent apoptosis inducer, AT-101 may be used as a chemosensitizer to overcome drug resistance of cancer cells.…”

“…AT-101 induced marked apoptosis with high efficiency in CDDP-resistant head and neck cancer cell lines that express high levels of Bcl-xl 74. There is a synergistic drug interaction between gossypol and gemcitabine in gemcitabine-resistant cancer cells with high Bcl-2 expression, and reversal of gemcitabine resistance by gossypol was associated with upregulation of the proapoptotic proteins phorbol-12-myristate-13-acetate-induced protein 1 (Noxa) and Mcl-1 and downregulation of the antiapoptotic proteins Bcl-2 and Bcl-xl 72. Activation of Noxa could lead to BH3 motif-dependent localization to the mitochondria and interaction with antiapoptotic Bcl-2 family members, resulting in activation of apoptosis.…”