Abaza Mohamed-Salah I, Bahman Abdul-Majeed, Al-Attiyah Raja'a J
Department of Biological Sciences, Faculty of Science, Kuwait University, Safat 13060, Kuwait.
Department of Microbiology, Faculty of Medicine, Kuwait University, Safat 13060, Kuwait.
Int J Mol Med. 2014 Aug;34(2):513-32. doi: 10.3892/ijmm.2014.1795. Epub 2014 Jun 4.
Although the therapeutic efficacy of valproic acid (VPA) has been observed in patients with solid tumors, the very high concentration required to induce antitumor activity limits its clinical utility. The present study focused on the development of combined molecular targeted therapies using VPA and proteasome inhibitors (PIs: MG132, PI-1 and PR-39) to determine whether this combination of treatments has synergistic anticancer and chemosensitizing effects against colorectal cancer. Furthermore, the potential molecular mechanisms of action of the VPA/PI combinations were evaluated. The effects of VPA in combination with PIs on the growth of colorectal cancer cells were assessed with regard to proliferation, cell cycle, apoptosis, reactive oxygen species (ROS) generation and the expression of genes that control the cell cycle, apoptosis and pro-survival/stress-related pathways. Treatment with combinations of VPA and PIs resulted in an additive/synergistic decrease in colorectal cancer cell proliferation compared to treatment with VPA or PIs alone. The combination treatment was associated with a synergistic increase in apoptosis and in the number of cells arrested in the S phase of the cell cycle. These events were associated with increased ROS generation, pro-apoptotic gene expression and stress-related gene expression. These events were also associated with the decreased expression of anti-apoptotic genes and pro-survival genes. The combination of VPA with MG132 or PI-1 enhanced the chemosensitivity of the SW1116 (29-185‑fold) and SW837 (50-620-fold) colorectal cancer cells. By contrast, the combination of VPA/PR-39 induced a pronounced increase in the chemosensitivity of the SW837 (16-54-fold) colorectal cancer cells. These data provide a rational basis for the clinical use of this combination therapy for the treatment of colorectal cancer.
尽管在实体瘤患者中已观察到丙戊酸（VPA）的治疗效果，但诱导抗肿瘤活性所需的极高浓度限制了其临床应用。本研究聚焦于开发使用VPA和蛋白酶体抑制剂（PIs：MG132、PI-1和PR-39）的联合分子靶向疗法，以确定这种联合治疗对结直肠癌是否具有协同抗癌和化学增敏作用。此外，还评估了VPA/PI组合潜在的分子作用机制。从增殖、细胞周期、凋亡、活性氧（ROS）生成以及控制细胞周期、凋亡和促生存/应激相关途径的基因表达方面，评估了VPA与PIs联合对结直肠癌细胞生长的影响。与单独使用VPA或PIs治疗相比，VPA和PIs联合治疗导致结直肠癌细胞增殖呈相加/协同性降低。联合治疗与凋亡协同增加以及细胞周期S期阻滞细胞数量增加相关。这些事件与ROS生成增加、促凋亡基因表达和应激相关基因表达增加有关。这些事件还与抗凋亡基因和促生存基因表达降低有关。VPA与MG132或PI-1联合增强了SW1116（29 - 185倍）和SW837（50 - 620倍）结直肠癌细胞的化学敏感性。相比之下，VPA/PR-39联合诱导SW837（16 - 54倍）结直肠癌细胞的化学敏感性显著增加。这些数据为这种联合疗法用于治疗结直肠癌的临床应用提供了合理依据。
