The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.
Biochem Pharmacol. 2020 Jan;171:113716. doi: 10.1016/j.bcp.2019.113716. Epub 2019 Nov 18.
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.
黑色素瘤是最具侵袭性的恶性肿瘤之一。药物耐药性和毒性限制了达卡巴嗪等黑色素瘤化疗药物的临床疗效。因此，迫切需要开发用于治疗黑色素瘤的化疗药物。RJT-101 显著抑制黑色素瘤细胞的增殖，然而对非恶性细胞的细胞毒性低。RJT-101 诱导细胞凋亡、DNA 损伤和 G2/M 期阻滞，从而抑制肿瘤生长、体内肺转移，并延长荷瘤小鼠的存活时间。RJT-101 可以通过蛋白酶体系统阻断拓扑异构酶 I（Top1）的活性并诱导其降解。有趣的是，Top1 在黑色素瘤细胞中过度表达，而非恶性细胞中则没有。Top1 的敲低抑制黑色素瘤细胞的生长，并诱导黑色素瘤细胞的凋亡和 DNA 损伤。RJT-101 通过抑制 Top1 诱导 DNA 损伤和凋亡，有效抑制黑色素瘤细胞（包括vemurafenib 耐药黑色素瘤细胞）的体外和体内增殖，表明 RJT-101 值得进一步临床评估。
