Abstract B38: A novel palladacycle complex with anti-cancer activity against breast cancer and melanomas also exhibits potent cytotoxicity in a range of sarcomas

Abstract

Abstract Cisplatin and second-generation alternatives to cisplatin, represent some of the most active and clinically useful agents in the treatment of cancer. However, their application in the clinic is marred by side-effects and drug resistance. We have identified the binuclear palladacycle, AJ-5, as a lead anticancer compound with potent activity against advanced melanomas and estrogen receptor -positive and -negative breast cancers. AJ-5 displayed an IC50 of 0.2μM in melanoma and breast cancer cell lines which was 50 fold less than that for cisplatin and our in vivo results show that it efficiently reduces melanomas in nude mice without any obvious side effects. AJ-5 also showed activity against breast cancer stem cells which are associated with drug-resistance and often not targeted by traditional chemotherapeutic agents. This study investigates the potential of AJ-5 as an anti-cancer agent in sarcomas, which are a heterogeneous group of neoplasms that account for approximately 21% of paediatric malignancies and treatment outcomes for patients with metastatic disease are dismal. Cytotoxicity assays were performed and sub-micromolar IC50 concentrations were obtained for rhabdomyosarcoma, chondrosarcoma, liposarcoma, synovial sarcoma and osteosarcoma. Clonogenic assays show that AJ-5 greatly compromises the long-term ability of the sarcoma cells to survive and proliferate. To determine the underlying molecular mechanisms by which AJ-5 exerts its cytotoxicity, western blot analyses were performed with antibodies to key proteins involved in the DNA damage response in rhabdomyosarcoma cell lines. The results show that AJ-5 induces high levels of γH2AX, a marker of double-stranded DNA breaks, and that it may exert it's cytotoxicity through the p38 MAP kinase stress pathway. Furthermore, Annexin VFITC/propidium iodide staining, Caspase Glo assays and western blotting demonstrated that AJ-5 induce intrinsic and extrinsic apoptosis more effectively than doxorubicin, a drug currently used in the treatment of rhabdomyosarcomas. AJ-5 treatment also led to autophagy as confirmed by the formation of autophagosomes, increased levels of LC3-II and the presence of LC3 puncta. Finally, pharmacokinetic studies show that AJ-5 has a promising half-life of 11.2 hours in mice and in addition its volume of distribution is high and its clearance is low while its intraperitoneal absorption is good. Thus the PK data correlates well with our observed efficacy of the drug in our mouse model. Together these findings suggest that AJ-5 may be an effective chemotherapeutic for treating a range of drug-resistant and advanced cancers. Citation Format: Jenna Bleloch, Reyna Ballim, Angelique Blanckenberg, Selwyn Mapolie, Serah Kimani, Sharon Prince. A novel palladacycle complex with anti-cancer activity against breast cancer and melanomas also exhibits potent cytotoxicity in a range of sarcomas [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B38.