Overcoming drug resistance in cancer therapy

23 Nov 2015 NUS researchers developed new platinum-based anticancer prodrugs designed to overcome multidrug resistance in targeted cancer cells.

Chemotherapy is an important weapon in the fight against cancer, particularly in the treatment of late stage malignancies when the disease has spread throughout the patient’s body. Amongst the range of anticancer drugs available, platinum-based agents are particularly prominent because they are highly effective and widely prescribed, accounting for more than half of the drugs used in the clinic. However, some cancers can develop multidrug resistance (MDR) by acquiring selective cellular adaptations to resist programmed cell death by apoptosis. Gastric cancer for example, a common cancer in Asia, is poorly responsive to chemotherapy due in part to the onset of apoptosis-resistance. Because most anticancer drugs work through apoptosis induction, finding new drug candidates that can induce non-apoptotic types of programmed cell death may be a way to circumvent the prevalence of MDR.

A team led by Prof ANG Wee Han from the Department of Chemistry has developed a class of platinum-peptide prodrugs that deliver cisplatin or oxaliplatin selectively to cancer cells by targeting the human epidermal growth factor receptor 2 (HER2) pathway. Human epidermal growth factor receptor 2 (HER2) is a clinically-validated receptor that is overexpressed in certain breast and gastric cancers. Peptides that mimic HER2 antibodies were coupled to platinum scaffolds containing cisplatin or oxaliplatin and the new conjugates were highly efficient in delivering the platinum payload to HER-positive cells, while ignoring cells with low HER2 expression. The researchers also discovered that these platinum-peptide constructs caused cell death by necrosis as a result of the massive platinum influx. This unusual form of cell-killing, targeted necrosis, is rarely reported in the literature. Importantly, the researchers showed that the new prodrugs can be harnessed to bypass apoptosis pathways to defeat dysfunctional MDR cancer cells, paving the way for the next generation of more effective metallodrugs with broader spectrum of activity.

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Figure shows the platinum prodrug of cisplatin containing a HER2-targeting peptide is capable of bypassing apoptosis and selectively inducing targeted necrosis in HER2-positive NCI-N87 gastric cancer cells. [Image credit : ANG Wee Han]

 

Reference

Wong DYQ, Lim JH, Ang WH. “Induction of Targeted Necrosis with HER2-targeted Platinum(IV) Anticancer Prodrugs.” Chemical Science. 6 (2015) 3051.