Kangwan Napapan, Park Jong-Min, Kim Eun-Hee, Hahm Ki Baik
Cancer Prevention Research Center, CHA University School of Medicine, Seoul, Korea.
J Cancer Prev. 2014 Jun;19(2):89-6. doi: 10.15430/JCP.2014.19.2.89.
Cellular quiescence is a state of reversible cell cycle arrest and is associated with a low metabolic state featured with decreased glycolysis, reduced translation rates, and activation of autophagy, fundamentally to provide nutrients for cell survival similar as seen in hybernation. As signal for quiescence, inactivating the target of rapamycin kinase and resulting reduced cell growth and biosynthesis are essential, but cellular quiescence is not always associated with reduced metabolism since it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. However, in cancer cells, overcoming intrinsic and acquired resistance of cancer stem or cancer dormancy cells to current clinical treatments can be reversed with the acquisition of chemoquiesence. The development of new drug combinations or strategy to treat the highly aggressive and metastatic cancers including relapsed leukaemias, melanoma and head and neck, brain, lung, breast, ovary, prostate, pancreas as well as gastrointestinal cancers which remain incurable in the clinic in spite of aggressive therapies, can be accelerated with the introduction of chemoquiescence agent, for which cancer stem cells or tumor dormancy should be eradicated or removed. Recently potential applications of metformin or chloroquine as well as the potential drugs under investigation such as proton pump inhibitor, sonic hedgehog inhibitor, and Akt inhibitor, are actively investigated in this field of chemoquiescence to achieve cancer cure far beyond those of chemoprevention. In this review article, the evolving concept of chemoquiescence or cancer dormancy will be introduced accompanied by a description of novel target drug development.
细胞静止是一种可逆的细胞周期停滞状态，与低代谢状态相关，其特征为糖酵解减少、翻译速率降低和自噬激活，从根本上来说是为细胞存活提供营养，类似于冬眠状态。作为静止信号，使雷帕霉素激酶靶点失活并导致细胞生长和生物合成减少至关重要，但细胞静止并不总是与代谢降低相关，因为也有可能实现一种细胞静止状态，其中葡萄糖摄取、糖酵解和通过中心碳代谢的通量并未降低。然而，在癌细胞中，通过获得化学静止可以逆转癌症干细胞或癌症休眠细胞对当前临床治疗的内在和获得性抗性。引入化学静止剂可以加速开发新的药物组合或策略，以治疗包括复发性白血病、黑色素瘤以及头颈部、脑、肺、乳腺、卵巢、前列腺、胰腺以及胃肠道癌症等高度侵袭性和转移性癌症，尽管进行了积极治疗，但这些癌症在临床上仍然无法治愈，为此应根除或清除癌症干细胞或肿瘤休眠细胞。最近，二甲双胍或氯喹以及正在研究的潜在药物如质子泵抑制剂、音猬因子抑制剂和Akt抑制剂在化学静止领域的潜在应用正在积极研究中，以实现远远超出化学预防的癌症治愈。在这篇综述文章中，将介绍化学静止或癌症休眠这一不断演变的概念，并描述新型靶向药物的开发。
