Mutation of tumor suppressor p53, which exhibits oncogenic gain-of-function (GOF) and promotes tumor progression, emerges as a therapeutic target for approximately 50% of all cancer cases. However, it is still unclear whether it is possible to restore GOF of p53 mutants without heterotetramer effect, as this often eliminates the efficacy of current approaches used to restore p53 function in p53 mutant cancers. Ceramide, an active sphingolipid metabolite, has pro-apoptotic effects on cancer cells but the hydrophobicity it has limits to develop ceramide as therapeutic agents. Here, we report that the ceramide-rubusoside (Cer-RUB), an ultrasmall nanomicelles enhances the bioavailability of C6-ceramide in vivo and restores wild-type p53 expression and its function in tumor suppression. We found that Cer-RUB nanomicelles enhanced the aqueous solubility of ceramide by 2,000-folds (2 mg/ml vs. <1.0 μg/ml), presented mono-disperse with an average particle sizes of 4 nm in cell culture medium, and elongated ceramide activity, due to a decrease in Cer-RUB glycosylation, compared to the C6-ceramide. More interestingly, Cer-RUB treatments (0.6 μM; 1 mg/kg) restored wild-type p53 expression documented in protein levels of phosphor-p53 and p53 responsive genes (p21, Bax) in cancer cell lines carrying R248G and R273H missense mutants and in heterozygous transgenic mice of 129S4-Trp53tm2.1Tyj. Cer-RUB significantly sensitized the resistance of these cells to anticancer drugs and eliminated cancer stem cells in cell culture and in tumor-bearing mice. This study indicates that Cer-RUB is a new approach to effectively target p53 mutant cancers.

Citation Format: Yong-Yu Liu, Zhijun Liu, Sachin K. Khiste, Salman B. Hosain. Ceramide-Rubusoside, an Ultrasmall Nanomicells Effectively Restores p53 Expression in the Missense Mutant Cancer Cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A19.