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New Anti-Cancer Drug Candidate Induces Cell Death Through Novel Mechanism

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A recent study published in the journal Toxicology and Applied Pharmacology has unveiled a new discovery in the fight against liver cancer. Researchers have identified a novel mechanism through which the anti-cancer drug candidate CBL0137 induces cell death in liver cancer cells. This discovery could pave the way for new therapeutic strategies in treating liver cancer, offering hope to patients and medical professionals alike.

CBL0137 is a small molecular anti-cancer drug candidate that has shown efficacy in preventing and delaying various types of cancers, including mammary tumours, colorectal adenocarcinoma, renal cell carcinoma, and human hepatocellular carcinoma (HCC). It has been shown that CBL0137 can cause apoptosis, which is a type of planned cell death, by activating the NF-κB pathway and the tumour suppressor protein p53. However, the potential of CBL0137 to induce necroptosis, another form of programmed cell death, remained unexplored until now.

The study, conducted by a team of researchers led by Jun Li and colleagues from the State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, and the University of Chinese Academy of Sciences, investigated whether CBL0137 could induce necroptosis in liver cancer cells. Necroptosis is a type of cell death that is different from apoptosis. Certain signaling pathways that involve proteins like RIPK1, RIPK3, and MLKL are in charge of controlling it.

It was found that CBL0137 greatly increased the production of left-handed Z-DNA structures, which are not as common as right-handed B-DNA structures. These cells came from people with liver cancer. This Z-DNA formation was confirmed using a Z-DNA specific antibody assay. The research also showed that treating cells with CBL0137 increased the levels of two proteins: ZBP1 and ADAR1.

The researchers found that blocking caspases, which are proteins that help with apoptosis, made CBL0137-induced necroptosis much more likely to happen. According to flow cytometry analysis, there was an increase in late apoptosis and necrosis to support this. Moreover, CBL0137 was found to induce the expression of necroptosis-related proteins RIPK1, RIPK3, and MLKL.

The study proposed that CBL0137-induced necroptosis in liver cancer cells occurs through the activation of the ZBP1/RIPK1/RIPK3/MLKL pathway, mediated by the induction of Z-DNA structures. This is the first report of CBL0137 causing necroptosis through Z-DNA in liver cancer cells.

The findings of this study have significant implications for cancer therapy. Necroptosis is known to be highly immunogenic, meaning it can stimulate an immune response against cancer cells. This characteristic makes necroptosis a promising target for cancer immunotherapy. The ability of CBL0137 to induce both apoptosis and necroptosis suggests that it could be effective in treating cancers that are resistant to apoptosis-inducing therapies.

The study highlights the potential of targeting Z-DNA structures and their binding proteins as a therapeutic strategy. The formation of Z-DNA and the subsequent activation of necroptosis pathways could provide a new avenue for developing anti-cancer drugs.

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