Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, New York.
Department of Oral Biology and Pathology, Stony Brook University, Stony Brook, New York.
Mol Carcinog. 2018 Sep;57(9):1130-1143. doi: 10.1002/mc.22830. Epub 2018 May 8.
Pancreatic Cancer (PC) is a deadly disease in need of new therapeutic options. We recently developed a novel tricarbonylmethane agent (CMC2.24) as a therapeutic agent for PC, and evaluated its efficacy in preclinical models of PC. CMC2.24 inhibited the growth of various human PC cell lines in a concentration and time-dependent manner. Normal human pancreatic epithelial cells were resistant to CMC2.24, indicating selectivity. CMC2.24 reduced the growth of subcutaneous and orthotopic PC xenografts in mice by up to 65% (P < 0.02), and the growth of a human patient-derived tumor xenograft by 47.5% (P < 0.03 vs vehicle control). Mechanistically, CMC2.24 inhibited the Ras-RAF-MEK-ERK pathway. Based on Ras Pull-Down Assays, CMC2.24 inhibited Ras-GTP, the active form of Ras, in MIA PaCa-2 cells and in pancreatic acinar explants isolated from Kras mutant mice, by 90.3% and 89.1%, respectively (P < 0.01, for both). The inhibition of active Ras led to an inhibition of c-RAF, MEK, and ERK phosphorylation by 93%, 91%, and 87%, respectively (P < 0.02, for all) in PC xenografts. Furthermore, c-RAF overexpression partially rescued MIA PaCa-2 cells from the cell growth inhibition by CMC2.24. In addition, downstream of ERK, CMC2.24 inhibited STAT3 phosphorylation levels at the serine 727 residue, enhanced the levels of superoxide anion in mitochondria, and induced intrinsic apoptosis as shown by the release of cytochrome c from the mitochondria to the cytosol and the further cleavage of caspase 9 in PC cells. In conclusion, CMC2.24, a potential Ras inhibitor, is an efficacious agent for PC treatment in preclinical models, deserving further evaluation.
胰腺癌（PC）是一种致命疾病，需要新的治疗选择。我们最近开发了一种新型三羰基甲烷试剂（CMC2.24）作为 PC 的治疗剂，并在 PC 的临床前模型中评估了其疗效。CMC2.24 以浓度和时间依赖的方式抑制各种人 PC 细胞系的生长。正常的人胰腺上皮细胞对 CMC2.24 具有抗性，表明其具有选择性。CMC2.24 使小鼠的皮下和原位 PC 异种移植的生长减少了高达 65%（P<0.02），并使人类患者来源的肿瘤异种移植的生长减少了 47.5%（P<0.03 与载体对照）。从机制上讲，CMC2.24 抑制了 Ras-RAF-MEK-ERK 通路。基于 Ras 下拉测定，CMC2.24 抑制了 MIA PaCa-2 细胞和从 Kras 突变小鼠分离的胰腺腺泡外植体中的 Ras-GTP，即活性形式的 Ras，分别为 90.3%和 89.1%（均为 P<0.01）。活性 Ras 的抑制导致 c-RAF、MEK 和 ERK 磷酸化分别抑制 93%、91%和 87%（均为 P<0.02）在 PC 异种移植中。此外，c-RAF 的过表达部分挽救了 MIA PaCa-2 细胞免受 CMC2.24 的细胞生长抑制。此外，在 ERK 下游，CMC2.24 抑制了丝氨酸 727 残基处的 STAT3 磷酸化水平，增强了线粒体中超氧阴离子的水平，并诱导了内在凋亡，如线粒体中的细胞色素 c 从线粒体释放到细胞质以及进一步裂解 caspase 9 在 PC 细胞中。总之，CMC2.24 是一种潜在的 Ras 抑制剂，作为一种有效的 PC 治疗剂在临床前模型中具有疗效，值得进一步评估。
