Wang Guan, Chen Shaohua, Edwards Holly, Cui Xinming, Cui Li, Ge Yubin
National Engineering Laboratory of AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P.R. China.
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Oncol Rep. 2014 Dec;32(6):2789-94. doi: 10.3892/or.2014.3525. Epub 2014 Oct 3.
Pancreatic cancer is an aggressive disease with a poor prognosis. Therefore, new treatment is urgently required. GX15-070 is a pan-Bcl-2 inhibitor which has shown promising antitumor activity in different malignancies. We previously demonstrated that clinically achievable concentrations of GX15-070 caused growth arrest in pancreatic cancer cell lines. However, they only induced minimal levels of apoptosis. We hypothesized that GX15-070 induced autophagy in pancreatic cancer cells which blocked apoptosis. In this study, we investigated the effects of GX15-070 on autophagy and the antitumor activities of the combination of GX15-070 and chloroquine (CQ), an autophagy inhibitor, in six pancreatic cancer cell lines. We found that GX15-070 treatment indeed induced autophagy in 5 of the 6 pancreatic cancer cell lines, reflected by the conversion of LC3B-I to LC3B-II and detection of autophagosomes by transmission electron microscopy. Furthermore, we found additive to synergistic antitumor interactions in all six cell lines by MTT assays. CQ significantly enhanced GX15-070-induced apoptosis in the cell line models, possibly due to downregulation of Bcl-2, Bcl-xL and Mcl-1 in the cells by the two agents. These results provide compelling evidence for the further development of the combination of GX15-070 and CQ in pancreatic cancer.
胰腺癌是一种侵袭性疾病，预后较差。因此，迫切需要新的治疗方法。GX15-070是一种泛Bcl-2抑制剂，已在不同恶性肿瘤中显示出有前景的抗肿瘤活性。我们之前证明，临床可达到的GX15-070浓度可导致胰腺癌细胞系生长停滞。然而，它们仅诱导了最低水平的细胞凋亡。我们推测GX15-070在胰腺癌细胞中诱导自噬，从而阻断细胞凋亡。在本研究中，我们调查了GX15-070对自噬的影响以及GX15-070与自噬抑制剂氯喹（CQ）联合使用在六种胰腺癌细胞系中的抗肿瘤活性。我们发现，GX15-070处理确实在6种胰腺癌细胞系中的5种中诱导了自噬，这通过LC3B-I向LC3B-II的转化以及透射电子显微镜检测自噬体得以体现。此外，我们通过MTT试验发现，在所有六种细胞系中均存在相加至协同的抗肿瘤相互作用。CQ在细胞系模型中显著增强了GX15-070诱导的细胞凋亡，这可能是由于这两种药物下调了细胞中的Bcl-2、Bcl-xL和Mcl-1。这些结果为进一步开发GX15-070与CQ联合用于胰腺癌治疗提供了有力证据。
