ROS Targeted Therapy for Lethal Prostate Cancer

ROS 靶向治疗致命性前列腺癌

• 批准号: 10322179
• 负责人: RUOXIANG WANG
• 金额: $ 22.95万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322179
• 关键词: Address; American; Androgen Antagonists; Antimalarials; Antineoplastic Agents; Apoptosis; Apoptotic; Artemisinins; Biological; Biological Availability; Biological Process; Blood; Cancer Etiology; Carbocyanines; Carrier Proteins; Castration; Cause of Death; Cell Death; Cell model; Cessation of life; Chemicals; Chemoresistance; Collaborations; Conjugating Agent; Detection; Development; Disease; Drug Delivery Systems; Drug Kinetics; Drug Sensitization; Drug resistance; Dyes; Family; Foundations; Future; Goals; Growth; Homeostasis; Hour; Hydroxyl Radical; Hypoxia Inducible Factor; In Vitro; Isotopes; Knowledge; Label; Lead; Ligand Binding; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Mitochondria; Modeling; Mus; Near-infrared optical imaging; Neoplasm Metastasis; Normal tissue morphology; OATP Transporters; Organ; Organelles; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Primary Neoplasm; Production; Property; Prostate Cancer therapy; Radio; Reactive Oxygen Species; Regulation; Reporting; Resistance; Scientist; Singlet Oxygen; Solid; Specific qualifier value; Specificity; Structure-Activity Relationship; Superoxides; Surface; Testing; Therapeutic; Therapeutic Intervention; Tissues; Treatment Efficacy; Up-Regulation; advanced prostate cancer; anti-cancer therapeutic; bioluminescence imaging; cancer cell; cancer diagnosis; cancer drug resistance; cancer therapy; castration resistant prostate cancer; chemical property; chemotherapy; comparative; design; differential expression; drug-sensitive; effective therapy; effectiveness evaluation; effectiveness study; hormone therapy; image guided; imaging modality; improved; in vitro testing; in vivo; innovation; men; molecular imaging; mortality; mouse model; neoplastic cell; novel; prostate cancer cell; prostate cancer cell line; prostate cancer metastasis; prostate cancer prevention; prostate cancer progression; receptor binding; refractory cancer; side effect; small molecule; targeted delivery; targeted treatment; tool; transcription factor; tumor; tumor growth; tumor hypoxia; uptake

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.

项目总结

项目成果

Breast Cancer MCF-7 Cells Acquire Heterogeneity during Successive Co-Culture with Hematopoietic and Bone Marrow-Derived Mesenchymal Stem/Stromal Cells.

• DOI: 10.3390/cells11223553
• 发表时间: 2022-11-10
• 期刊: CELLS
• 影响因子: 6
• 作者: Wang, Ruoxiang;Wang, Xudong;Yin, Liyuan;Yin, Lijuan;Chu, Gina Chia-Yi;Hu, Peizhen;Ou, Yan;Zhang, Yi;Lewis, Michael S.;Pandol, Stephen J.
• 通讯作者: Pandol, Stephen J.

A cisplatin conjugate with tumor cell specificity exhibits antitumor effects in renal cancer models.

• DOI: 10.1186/s12885-023-10878-3
• 发表时间: 2023-06-02
• 期刊: BMC CANCER
• 影响因子: 3.8
• 作者: Mrdenovic, Stefan;Wang, Yanping;Yin, Lijuan;Chu, Gina Chia-Yi;Ou, Yan;Lewis, Michael S.;Heffer, Marija;Posadas, Edwin M.;Zhau, Haiyen E.;Chung, Leland W. K.;Edderkaoui, Mouad;Pandol, Stephen J.;Wang, Ruoxiang;Zhang, Yi
• 通讯作者: Zhang, Yi

Circulating Fatty Objects and Their Preferential Presence in Pancreatic Cancer Patient Blood Samples.

• DOI: 10.3389/fphys.2022.827531
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Wang R;Nissen NN;Zhang Y;Shao C;Chu CY;Huynh C;Posadas EM;Tomlinson JS;Lewis MS;Pandol SJ
• 通讯作者: Pandol SJ