Suppression of Reserve MCM Complexes Chemosensitizes to Gemcitabine and 5-Fluorouracil.
Suppression of Reserve MCM Complexes Chemosensitizes to Gemcitabine and 5-Fluorouracil.
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DOI：
10.1158/1541-7786.mcr-14-0464
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Alexandrow MG
中科院分区：
文献类型：
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作者：
Bryant VL;Elias RM;McCarthy SM;Yeatman TJ;Alexandrow MG
胰腺导管腺癌（PDAC）是最致命的癌症之一，很难用传统的化疗方案治疗。吉西他滨和5-氟尿嘧啶（5-FU）用于PDAC的管理，通过间接阻断复制叉起作用。然而，这些药物在抑制疾病进展方面并不是非常有效，这表明需要开发创新的治疗方法。最近的研究表明，抑制MCM解旋酶可能提供了一种新的手段，使癌细胞对抑制复制叉进展的化疗药物敏感。哺乳动物细胞在DNA上组装的MCM复合物比启动s期所需的要多。在复制应激条件下，过量的MCM复合物作为备用起始位点发挥作用。目前的研究提供了明确的证据，表明过量/备用MCM复合物的共同抑制使PDAC肿瘤细胞系对吉西他滨和5-FU都敏感，与单独使用药物相比，导致增殖能力丧失增加。这是因为MCM水平的降低阻碍了暴露于药物的肿瘤细胞DNA复制的有效恢复。在吉西他滨存在的情况下，PDAC肿瘤细胞比非肿瘤的永生化上皮细胞对MCM的丧失更敏感。同样，当暴露于交联剂奥沙利铂或拓扑异构酶抑制剂依托泊苷时，MCM复合物的共抑制发生时，结肠肿瘤细胞的存活率降低。这些研究表明，抑制MCM复合物的后备补体提供了一种有效的增敏方法，有可能提高PDAC和其他癌症临床治疗中使用的药物的治疗指数。
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is very difficult to treat with conventional chemotherapeutic regimens. Gemcitabine and 5-fluorouracil (5-FU) are used in the management of PDAC and act by indirectly blocking replicative forks. However, these drugs are not highly effective at suppressing disease progression, indicating a need for the development of innovative therapeutic approaches. Recent studies indicate that suppression of the MCM helicase may provide a novel means to sensitize cancer cells to chemotherapeutic agents that inhibit replicative fork progression. Mammalian cells assemble more MCM complexes on DNA than are required to start S-phase. The excess MCM complexes function as back-up initiation sites under conditions of replicative stress. The current study provides definitive evidence that co-suppression of the excess/back-up MCM complexes sensitizes PDAC tumor lines to both gemcitabine and 5-FU, leading to increased loss of proliferative capacity compared to drugs alone. This occurs because reduced MCM levels prevent efficient recovery of DNA replication in tumor cells exposed to drug. PDAC tumor cells are more sensitive to MCM loss in the presence of gemcitabine than are non-tumor, immortalized epithelial cells. Similarly, colon tumor cells are rendered less viable when co-suppression of MCM complexes occurs during exposure to the crosslinking agent oxaliplatin or topoisomerase inhibitor etoposide. These studies demonstrate that suppressing the back-up complement of MCM complexes provides an effective sensitizing approach with the potential to increase the therapeutic index of drugs used in the clinical management of PDAC and other cancers.