ROS Targeted Therapy for Lethal Prostate Cancer

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PROJECT SUMMARY Prostate cancer (PC) is the second leading cause of cancer mortality in American men. Current therapeutics only show marginal efficacy and are often associated with serious side effects and drug resistance that contribute to patient mortality. Cancer drug resistance is one of the most challenging difficulties that needs to be addressed with innovative mechanistic knowledge and tactical application. Reactive oxygen species (ROS), such as superoxide anion (O2−), singlet oxygen (1O2) and hydroxyl radical (·OH), are highly active metabolic by-products, whose homeostasis is maintained by redox regulation. High levels of ROS can cause tissue damages and even cell death. Though small molecule reactive oxygen generating agents (ROSG) that enhance intracellular ROS levels may thus serve as anti-tumor therapeutics, the in vivo efficacy of these compounds in cancer therapy is severely impeded by their unfavorable pharmacokinetic properties, low bioavailability, and their poor targeting property specifically to tumor cells. In this regard, we have discovered that certain some specified near infrared (NIR) heptamethine carbocyanine dye (HMCD) can enter cancer cells with high selectivity via organic anion transporting polypeptide (OATP) family of carrier proteins, which are differentially expressed in cancer cells while the expression can be further enhanced by intra-tumoral hypoxia through upregulation of transcription factor of the hypoxia inducible factor (HIF-1α). To improve the efficacy of ROS-mediated cancer therapy, we sought to conjugate small molecule ROSG with cancer-specific HMCD for cancer cell targeting and delivery. This innovative project will allow us to test the potential impact of delivering small molecule ROSG directly to cancer cells to induce apoptosis. We hypothesize that HMCD-ROSG kills cancer cells in vitro; and will also be effective in vivo for targeted treatment of lethal PCs. The unique mechanism of action is mediated by ROS production in cancer cell subcellular organelles, disrupting vital biologic function to elicit apoptosis. Our preliminary results indicated that, compared with hormonal therapy and chemotherapy, PC cells could be killed more effectively by HMCD-ROSG. The synthesis and characterization of HMCD-ROSG conjugates will be performed and the biological activities of these new chemical entities will be tested in vitro with drug-sensitive and drug-resistant PC cells lines and in vivo with mouse models. We will employ NIR and bioluminescence imaging modalities as detection tools to assess specificity of the HMCD-ROSG conjugates into tumors and to study the effectiveness of these novel compounds as anti-cancer therapeutic and sensitizing agents for high efficacy on prevention of PC progression and metastasis. The proposed project will be performed by a scientific collaboration between a chemist and cancer scientist. The proposal will provide a solid foundation and new aspect to the ROS-mediated therapy as a potent therapeutic intervention for advanced and castration-resistant PC and metastasis.