Anticancer metallocomplexes with non-classical modes of activity
Platinum-based anticancer drugs, cisplatin, carboplatin and oxaliplatin, are some of the most effective chemotherapies used in clinic. Their cytotoxic activity against cancer stems from a combination of processes including cell entry, drug activation, DNA-binding and transcription inhibition, resulting in apoptotic cell death. Due to limitations in platinum-based therapy arising from toxicity, high side-effects and incidence of drug resistance, there have been a renewed interest in studying other metallocomplexes as alternatives and to revisiting some of the earlier assumptions. There is evidence that for these cytotoxics, at least part of the observed clinical therapeutic efficacy of these agents actually hinges on its “off-target” immunostimulating mechanisms. Because cytotoxic chemotherapeutic drugs have been thought of as immunosuppressive, they have been generally discounted as potential immunotherapeutic agents. Our preliminary work identifying new metal—based complexes that induce immunogenic cell death, a cell death mechanism that specifically elicit an immunological response, will be discussed. I will also report a rationally-designed platinum(IV)-peptide prodrug conjugate that activates immune cells via the FPR-1/2 pathway. These efforts pave the way for platinum compounds as immuno-chemotherapeutic agents for cancer therapy. I will also discuss our new efforts towards imaging the reduction of platinum(IV) prodrug complexes in vitro.
Wee Han Ang graduated from Imperial College, UK in 1995 with BSc(Hons) to serve in the navy. He was retired from service in 2003 and returned to academia to pursue his PhD studies at EPFL, Switzerland under the supervision of Paul Dyson. He then moved to MIT, US as a postdoctoral research fellow in the laboratory of Stephen Lippard, where he studied the effects of Pt-DNA adducts on RNA transcription. He joined the National University of Singapore in 2009 as an assistant professor to embark on his independent academic career. He was promoted to associate professor with tenure in 2015. Wee Han is currently the deputy head of the department in charge of administration and student life. Concurrently, he is a faculty member of NUS graduate school of integrative sciences and engineering as well as a PI in the NUS’s Drug Development Unit.