Alternative strategy to overcoming drug resistance

17 Mar 2016 NUS scientists discover new organoruthenium anticancer complexes able to overcome multidrug resistance (MDR) by inducing alternative modes of cell death.

Chemotherapy is the mainstay in cancer therapy, either as a standalone treatment or in tandem with other treatment options. Most anticancer drugs used in chemotherapy act by inducing a common form of programmed cell death known as ‘apoptosis’. However, some cancers can adapt and become resistant to apoptosis, leading to multidrug resistance (MDR), one of the major impediments to the success of chemotherapy in many cancer types including gastric, ovarian and breast cancers. Given that most anticancer drugs work through induction of apoptosis, finding new drug candidates that can trigger alternative forms of programmed cell death may be a way to circumvent MDR and improve therapeutic outcomes.

Prof ANG Wee Han and his team from the Department of Chemistry in NUS, in collaboration with Dr Christian GAIDDON (U113 INSERM, France), have discovered two organoruthenium compounds with unique modes-of-action distinct from current clinical drugs such as cisplatin which act via apoptosis by targeting nuclear DNA. Cisplatin, a platinum-based chemotherapeutic drug, is currently used extensively for the treatment of a wide range of malignancies such as testicular cancer. These two new ruthenium-based compounds were first discovered through screening of a large library of ruthenium compounds prepared using a novel combinatorial synthesis approach developed by the NUS team. Together with the INSERM researchers, the team established that the compounds induced a non-apoptotic form of programmed cell death via the activation of endoplasmic reticulum (ER) stress pathways. Although the specific types of cell death induced have yet to be identified, the ‘non-apoptotic’ cell death was shown to induce cytotoxicity in cells that exhibit the MDR phenotype and are resistant to classical anticancer drugs.

Researchers have long suggested that compounds that induced alternative modes of cell death may be the way forward in the treatment of resistant cancers. A number of reported metallocomplexes have previously demonstrated the ability to induce other cell death types. However, their ability to overcome drug resistance has not been well-rationalised and is rarely validated. This work represents one of the first few examples, paving the way for the next generation of effective metallodrugs with non-classical modes of activity.

“The next step would be to test these compounds in animal models for resistant cancers. Positive data in animal work would give us a stronger indication of their ability to bypass MDR mechanisms,” said Prof Ang with regards to the future direction of this research project.

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Figure shows the small change in the structure of RAS complexes was sufficient to induce differential ER stress pathway activations. Both lead to alternative (non-apoptotic) programmed cell death that bypasses drug resistance mechanisms. [Image credit: CHOW Mun Juinn]

 

Reference

Chow MJ, Licona C, Pastorin G, Mellitzer G, Ang WH, Gaiddon C. “Structural tuning of organoruthenium compounds allows oxidative switch to control ER stress pathways and bypass multidrug resistance” Chemical Science (2016)DOI: 10.1039/C6SC00268D.