Research Projects

The lack of effective cancer therapy, non-specific cytotoxicity, and chemotherapeutic resistance are major factors contributing to high fatalities in both humans and animals. To increase the therapeutic response and curb chemotherapeutic resistance, molecular mechanisms and therapeutic targets need to be identified. Modulating the cytoproliferative nature of P2RX7 receptors towards cytotoxic response in cancer cells by small molecule inhibitors (SMIs) could be a relevant strategy for effective cancer therapy. P2RX7 is a purinergic receptor overexpressed in macrophages, neuroglial cells, and tumor cells, which can be activated by high amounts of extracellular ATP (eATP) during chronic inflammation. Persistent exposure to elevated levels of eATP causes receptor desensitization, leading to pore over dilation and cell death. Cholesterol could be a compensatory player used by cancer cells to prevent receptor desensitization and offset the effects of eATP toxicity mediated P2RX7 pore over dilation. Cholesterol binding to the transmembrane domain (TMD) of P2RX7 has been shown to reduce activation and pore dynamics. However, cholesterol binding sites (CBS) and dynamical changes of their interaction have never been quantified. The current project hypothesizes that cancer cells may be using membrane cholesterol interaction with P2RX7 TMD to offset the effects of ATP toxicity by modulating pore dynamics. Targeting CBS with SMIs can abrogate the relationship between cholesterol and P2RX7 TMD, facilitating pore over dilation and ultimately aggravate cancer cell death. The aim is to identify CBS in P2RX7 TMD and target them with suitable SMIs to increase cancer cell death.

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