Ribonucleic acid (RNA) is fundamental to life. Acting between DNA and proteins in the central dogma of biology, RNA holds essential roles in coding, decoding, regulating and expressing genes. Despite the functional importance of RNA, most small molecule drugs against disease target protein or DNA. Our project aims to elucidate the interactions between the cancer drug, Cisplatin, and cellular RNA.
Cisplatin is a platinum-based chemotherapy medication first approved for medical use in 1978. Since then, Cisplatin has become an essential medicine in the treatment of lung cancer, mesothelioma, neuroblastoma, among other cancers, by lesioning cellular DNA by replacing Guanine nucleosides and, subsequently, triggering cell death.
While the mechanism of action is well understood for DNA, we hypothesize that Cisplatin may also have biological consequences on RNA since RNA is also comprised of Guanine nucleosides. We believe certain damage-response proteins may be bound to these Cisplatin modified RNA sequences aiding in their destruction, metabolism or localization.
Our research has depended on the total synthesis of a Cisplatin-like molecule containing chemical moieties useful for downstream biology. We are pursuing three strategies to elucidate the in vivo functionality of Cisplatin.
We are utilizing immunofluorescence to map where cisplatin localizes in cells. Moreover, we are deploying chemically modified RNA probes to capture the protein landscape on such lesions. We are also sequencing Cisplatin lesions on RNA to gauge any sequence-specific interactions.
Our project has the potential to expose new Cisplatin drug interactions, resistance mechanisms to Cisplatin treatments and uncover novel drug targets.