cinobufagin and Neoplasms

DNA topoisomerases are proved cancer therapeutic targets with clinically successful anticancer drugs for decades. However, the role of RNA topoisomerase (TOP3β) remained mysterious especially in cancer, and no targeted agent has been reported yet. In a target identification assay of anti-cancer compound using a modified DrugTargetSeqR strategy, mutation of TOP3B was detected in cancer cells acquired resistance to cinobufagin (CBG), a key compound of Huachansu that has been approved for cancer therapy in China. We demonstrated that CBG directly engaged with TOP3β, and promoted TOP3β depletion in wildtype but not mutant cancer cells. Notably, knockout of TOP3β in cancer cells significantly reduced tumor enlargement but not initiation, and inhibited colony formation upon nutrient deprivation. We also demonstrated that CBG induced formation of stress granule, RNA-loop and asymmetric DNA damages in cancer cells, and all these phenotypes were significantly attenuated in TOP3B knockout cells. Of note, examination of a panel of cancer cell lines revealed associations among cell growth inhibition and induction of DNA damage as well as TOP3B depletion upon CBG treatment. Our findings not only highlighted TOP3β as a promising therapeutic target of cancer, but also identified CBG as a lead chemical inhibitor of TOP3β for cancer therapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bufanolides; Cell Line, Tumor; Cell Survival; DNA Topoisomerases, Type I; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Topoisomerase I Inhibitors

Cinobufacini is extracted from the skins and parotid venom glands of the toad for treating symptoms like swelling and pain in ancient times. Nowadays, cinobifucini injection has also achieved satisfactory therapeutic effects on hepatocellular carcinoma (HCC) in China.. Our previous work found that bufothionine, an alkaloid abundant in cinobufacini injection, induced mitochondria-mediated apoptosis. In this work, the underlying effects of bufothionine on autophagy in HCC and its possible dependent pathway were investigated.. In vitro, CCK-8 and Hoechst staining assays showed that bufothionine inhibited SMMC7721 cell proliferation and promoted apoptosis at 100 μM. In vivo, bufothionine relieved symptoms of H. This is the first report showing that bufothionine might induce autophagy in HCC by inhibiting JAK2/STAT3 pathway, presenting a possible anti-cancer mechanism of bufothionine in cinobufacini injection.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Bufanolides; Cell Line, Tumor; Cell Proliferation; Humans; Indole Alkaloids; Interleukin-6; Janus Kinase 2; Liver Neoplasms, Experimental; Male; Mice; Neoplasms; Quinolinium Compounds; Signal Transduction; STAT3 Transcription Factor