RJT-101, a novel camptothecin derivative, is highly effective in the treatment of melanoma through DNA damage by targeting topoisomerase 1
RJT-101, a novel camptothecin derivative, is highly effective in the treatment of melanoma through DNA damage by targeting topoisomerase 1
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RJT-101是一种新型喜树碱衍生物，通过靶向拓扑异构酶1，通过DNA损伤治疗黑色素瘤非常有效
DOI：
10.1016/j.bcp.2019.113716
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发表时间：
2020-01-01
影响因子：
5.8
通讯作者：
Peng, Cong
中科院分区：
文献类型：
--
作者：
Lian, Chengxiang;Cao, Shousong;Peng, Cong
黑色素瘤是最具侵袭性的恶性肿瘤之一。耐药性和毒性限制了黑色素瘤化疗药物如达卡巴嗪的临床疗效。因此，迫切需要开发用于黑色素瘤治疗的化疗药物。RJT-101显著抑制黑色素瘤细胞的增殖，但对非恶性细胞的细胞毒性较低。RJT-101诱导细胞凋亡、DNA损伤和G2/M期阻滞，从而减少肿瘤生长、体内肺转移以及荷瘤小鼠的存活。RJT-101可阻断拓扑异构酶I（Top1）的活性，并通过蛋白酶体系统诱导其降解。有趣的是，与非恶性细胞相比，Top1在黑素瘤细胞中过表达。Top1的敲低抑制黑色素瘤细胞生长并诱导黑色素瘤细胞凋亡和DNA损伤。RJT-101通过抑制Top1诱导DNA损伤和凋亡，在体外和体内有效抑制黑色素瘤细胞（包括维罗非尼耐药黑色素瘤细胞）增殖，表明RJT-101值得进一步临床评价。
Melanoma is one of the most aggressive malignancies. Drug resistance and toxicity limits the clinical efficacy of melanoma chemotherapeutic drugs such as dacarbazine. Therefore, the development of chemotherapeutic agents for melanoma treatment is urgently needed. RJT-101 significantly inhibits the proliferation of melanoma cells, however has low cytotoxicity to non-malignant cells. RJT-101 induces apoptosis, DNA damage, and G2/M phase arrest, as a consequent, attenuates tumor growth, lung metastasis in vivo as well as prolongs survival of tumor bearing mice. RJT-101 could block topoisomerase I (Top1) activity as well as induce its degradation through proteasome system. Interestingly, Top1 is over-expressed in melanoma cells, compared to non-malignant cells. Knock down of Top1 suppresses melanoma cells growth and induces apoptosis and DNA damage in melanoma cells. RJT-101 effectively inhibits melanoma cells (including vemurafenib-resistant melanoma cells) proliferation in vitro and in vivo through the induction of DNA damage and apoptosis by inhibiting of Top1, indicating RJT-101 warrants further clinical evaluation.