RJT-101, a novel camptothecin derivative, is highly effective in the treatment of melanoma through DNA damage by targeting topoisomerase 1.

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.