Abstract 5555: Honokiol inhibits tumor growth in a xenograft melanoma mice model and activates the apoptotic signaling pathway in vivo.

Abstract

Abstract Melanoma is the deadliest type of skin cancer. For adults 25-29 years old, melanoma is the most common cancer, while it is the second most common cancer for 15-29 years old. Limited therapies are available for advanced stages; therefore, there is a need for development of new treatments for melanoma. Honokiol is a plant lignan extracted from the magnolia bark tree. Studies from our laboratory showed its chemopreventive effects in a UVB-induced skin cancer model, as well as in vitro pro-apoptotic effects in A431 squamous cancer cells, UACC-62 and SKMEL-2 human melanoma cell lines. In this study, the antineoplastic effects of honokiol were evaluated in vivo against the malignant melanoma cell lines UACC-62 that harbors mutated BRAF, CDK4i, PTEN and SKMEL-2 cells that presents NRAF, and TP53 mutated genes. The present study investigated the mechanism of honokiol-induced antitumoral effects in human melanoma UACC-62 and SKMEL-2 cells in two xenograft melanoma models in mice. UACC-62 and SKMEL-2 melanoma cells were subcutaneously grafted in nude mice, treatment groups received honokiol 50 mg/kg thrice a week and tumor growth was followed. After five to seven weeks, animals were euthanized and tumor tissue collected for gene profiling and western blots. The genetic expression of apoptotic biomarkers was assessed by qRT-PCR by using PCR arrays for the apoptotic pathway (SABiosciences, CA). After subcutaneous grafting of UACC-62 or SKMEL-2 human melanoma cells in the nude mice, the intraperitoneal administration of honokiol at 50 mg/kg body weight for five to seven weeks caused a significant reduction of tumor growth. Honokiol activated the apoptotic pathway in UACC-62 cells xenograft tumors in mice, as attested by the significant up-regulation of BAK1, BAX, CARD8, CASP10, CASP2, CASP6, CASP7, FADD, TNFRSF10B, TNFRSF25, TP53 and TP53BP2 transcripts. In the western blots from the UACC-62 cells tumors, there was an increase in the expression of CASP3, CASP7, CASP8, CASP6, cleaved CASP6 and CASP10 proteins in the honokiol treated group. In the tumors originated from the SKMEL-2 melanoma cells, a significant up-regulation of BAD, BAK1, BAX, NOD1, CARD6, CASP7, FADD, TNFRSF21 and TRAF3 transcripts was observed. The activation of the apoptotic pathway in the SKMEL-2 cells tumors by honokiol was further confirmed by western blots in the tumor lysates, where it was observed an increase in the activation of caspases and cleavage of PARP in the honokiol treated animals. Honokiol treatment exerted significant antitumor effects, including the activation of the apoptotic signaling pathway in UACC-62 and SKMEL-2 human melanoma cells in xenograft tumors in mice. These findings suggest that honokiol is a good candidate for further studies as a treatment for malignant melanoma. This work is supported by a Translational Cancer Center Research Grant, funded as 2010 Research Initiative Center by the State of South Dakota. Citation Format: Ruth F. Guillermo, Sreevidya Santha, Jonathan Stevens, Emily Coughlin, Pious Patel, Radhey S. Kaushik, Chandradhar Dwivedi. Honokiol inhibits tumor growth in a xenograft melanoma mice model and activates the apoptotic signaling pathway in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5555. doi:10.1158/1538-7445.AM2013-5555