Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
PLoS One. 2012;7(12):e50786. doi: 10.1371/journal.pone.0050786. Epub 2012 Dec 4.
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.
虽然吉西他滨在几种癌症类型中具有高度活性，但内在和获得性药物耐药性仍然是一个主要挑战。Bcl-2 的过表达与吉西他滨耐药性有关。本研究旨在确定在高表达 Bcl-2 的细胞系中，是否可以通过联合药物治疗来克服吉西他滨耐药性。我们的研究表明，在来自不同癌症的 10 个细胞系中，吉西他滨耐药（GEM-R）细胞系中观察到高基线 Bcl-2 表达。此外，在高 Bcl-2 表达的吉西他滨耐药（GEM-R）细胞系中观察到联合治疗的协同作用，但在吉西他滨敏感（GEM-S）细胞系中无论 Bcl-2 表达如何都没有观察到协同作用。棉酚处理导致抗凋亡基因如 Bcl-2 和 Bcl-xl 的表达减少，促凋亡基因 Noxa 的表达上调。此外，与单独使用吉西他滨相比，棉酚与吉西他滨联合使用导致抗凋亡基因的表达降低。GEM-R 和 GEM-S 细胞系中的基因表达谱表明，抗凋亡基因如 pAkt 和 PI3KR2 可能在吉西他滨耐药性中起重要作用，而促凋亡的 Bcl-2 相关基因（Bad、Caspase-6 和 Calpain-1）可能调节联合治疗中的协同相互作用。
