A Novel Chemically-Modified Curcumin (Cmc 2.24) Promotes Chemosensitivity In Neuroblastoma

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LAIntroductionThe chemically modified curcumin, CMC 2.24 (TRB-N0224, Traverse Biosciences Inc.), was designed to overcome the poor solubility, bioavailability, and biological potency of naturally occurring curcumin in an effort to achieve superior safety and efficacy in chronic inflammatory conditions and cancer. It has been demonstrated that CMC 2.24 can sensitize cancer cells that are otherwise refractory to chemotherapy. Patients with neuroblastoma, a highly lethal childhood cancer of the peripheral sympathetic nervous system, often have de novo chemotherapy resistance and therefore succumb rapidly to their disease. We hypothesize that chemoresistance in primary refractory neuroblastoma is mediated by anti-apoptotic mechanisms that can be overcome when conventional therapy is combined with CMC 2.24.Experimental ProceduresA heterogeneous panel of neuroblastoma cell lines was cultured under routine conditions and subjected to varying concentrations of CMC 2.24 to establish IC50s. Subsequent studies were focused on NB-EBc1, a MYCN non-amplified cell line, and IMR-5, a MYCN amplified cell line. IC50s were also generated for cisplatin as a single agent, and then when administered in combination with CMC 2.24. Whole protein cell lysates were extracted at 24, 48, and 72 hours after treatment and cell viability was measured by MTT proliferation assays.ResultsProliferation defects were observed in all neuroblastoma cell lines treated with CMC 2.24 as compared to vehicle (DMSO) control. Relatively cisplatin-resistant cell lines had diminished cell viability when CMC 2.24 was added in combination with cisplatin, suggesting a synergistic effect. Alterations in response to CMC 2.24 treatment occur in anti-apoptotic proteins survivin and BARD1, found to be upregulated in chemoresistant cell lines. Additional mechanistic evaluation is ongoing.ConclusionsThere is no known curative therapy for patients with primary refractory neuroblastoma. CMC 2.24 enhances chemosensitivity in a panel of neuroblastoma cell lines and may provide a new therapeutic approach that can overcome de novo chemotherapy resistance. Further mechanistic and in vivo studies are needed to facilitate clinical development of a promising novel anti-cancer agent.Citation Format: David Tauber, Basia Galinski, Raquel Castellanos, Joseph Scaduto, Francis Johnson, Lorne Golub, Daniel A. Weiser. A novel chemically-modified curcumin (CMC 2.24) promotes chemosensitivity in neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2481A.