Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Int J Oncol. 2012 Jul;41(1):76-82. doi: 10.3892/ijo.2012.1448. Epub 2012 Apr 26.
Colorectal cancer (CRC) is one of the most common cancers; however, the development of drugs to treat the condition has reached a plateau. Bortezomib (PS-341, Velcade®) is a proteasome inhibitor approved for the treatment of hematological malignancies, including multiple myeloma. A few trials of bortezomib, alone or in combination chemotherapy, for CRC patients have been reported; however, the results were largely inconclusive. This may be related to a lack of understanding of the drug's mechanism of action. Although bortezomib is reported to induce apoptosis and cell cycle arrest in various human cancer cells, the inhibitory mechanism involved is not clear. In this study, the effect of bortezomib as a treatment for human CRC was examined in vitro using three CRC cell lines. Bortezomib induced G2-M arrest in CRC cells. Investigation of G2-M phase-related cell cycle proteins involved in the response to bortezomib revealed that the ataxia telangiectasia mutated (ATM)-cell cycle checkpoint kinase 1 (CHK1) pathway, but not ATM and Rad3-related (ATR), was activated, resulting in the inactivation of cdc2. Bortezomib caused an increase in intracellular reactive oxygen species (ROS) and treatment with the ROS scavenger NAC inhibited phosphorylation of ATM leading to a decrease in the number of cells in G2-M phase. Thus, increased ROS levels after exposure to bortezomib resulted in ATM phosphorylation. In addition, knockdown of endogenous ATM by RNA interference resulted in decreased sensitivity to bortezomib. These results suggest that bortezomib induces G2-M arrest through ROS-inducible ATM phosphorylation and demonstrate that bortezomib is a potential candidate for further investigations in the treatment for CRC patients.
结直肠癌（CRC）是最常见的癌症之一；然而，用于治疗该疾病的药物的发展已经达到了一个瓶颈。硼替佐米（PS-341，Velcade®）是一种蛋白酶体抑制剂，已被批准用于治疗血液系统恶性肿瘤，包括多发性骨髓瘤。已经有一些关于硼替佐米单独或联合化疗治疗 CRC 患者的临床试验报告；然而，结果基本上没有定论。这可能与对药物作用机制的理解不足有关。尽管硼替佐米被报道在各种人类癌细胞中诱导细胞凋亡和细胞周期停滞，但涉及的抑制机制尚不清楚。在这项研究中，使用三种 CRC 细胞系在体外检查了硼替佐米作为治疗人类 CRC 的效果。硼替佐米诱导 CRC 细胞发生 G2-M 期阻滞。对参与硼替佐米反应的 G2-M 期相关细胞周期蛋白的研究表明，共济失调毛细血管扩张突变（ATM）-细胞周期检查点激酶 1（CHK1）途径被激活，但 ATM 和 Rad3 相关（ATR）途径未被激活，导致 cdc2 失活。硼替佐米导致细胞内活性氧（ROS）增加，用 ROS 清除剂 NAC 处理会抑制 ATM 的磷酸化，从而减少 G2-M 期的细胞数量。因此，硼替佐米暴露后 ROS 水平的增加导致 ATM 磷酸化。此外，通过 RNA 干扰敲低内源性 ATM 会导致对硼替佐米的敏感性降低。这些结果表明，硼替佐米通过 ROS 诱导的 ATM 磷酸化诱导 G2-M 期阻滞，并表明硼替佐米是进一步研究治疗 CRC 患者的潜在候选药物。
