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Invariant natural killer T (iNKT) cells represent a unique subpopulation of innate immune cells which have immune modulatory effects on many immune effector cells such as CD4 T cells and CD8 T cells. Alpha-galactosylceramide (a-GalCer) is a well-known iNKT-stimulating glycolipid. Using a-GalCer as a template, we have generated a more potent a-GalCer analog C34, which contains two aromatic rings at the acyl chain and demonstrated its anti-cancer effect on tumor bearing mice model. It has been reported that NKT cells killed cancer cell lines treated with chemotherapy agents through TRAIL- and FasL-mediated pathways. In this study, we evaluated the anti-cancer effects of chemotherapy and C34 on tumor-bearing mouse model. First, BALB/c mice bearing 4T1 breast cancer were injected with various dose of chemotherapy agents weekly x 5 and the sub-optimal dose of docetaxel and doxorubicin was determined to be 0.5 mg/Kg. Similarly, sub-optimal dose of cisplatin and docetaxel in TC1 lung cancer-bearing C57BL/6 mice was determined to be 1 mg/Kg and 2 mg/Kg, respectively. In both tumor models, the suboptimal dose of C34 was found to be 0.1 ug per mouse. The treatment schedules of combination of chemotherapy and C34 were examined by administration of C34 at the same day (0D), three days (-3D) and one day (-1D) before chemotherapy and one day (+1D) after chemotherapy. We observed a survival benefit in mice injected with C34 one day after docetaxel treatment in 4T1-bearing mice as compared to those treated with the other schedules. Moreover, the survival of mice was significantly prolonged when C34 was injected three days after cisplatin treatment in TC1-bearing mice (median survival: 46 days for cisplatin and 55 days for cisplatin+C34, log-rank test p = 0.041). In the 4T1 tumor microenvironment, we found the number of CD3+CD8+ T cells was significantly greater in mice treated with docetaxel+C34 (23,536 +/- 901.4) than those treated with docetaxel only (2,270 +/- 1,536, t-test P < 0.0001). In addition, the number of PD1+ CD8 T cells was slightly higher, but did not reach statistical significance (t-test p = 0.3), in mice treated with docetaxel+C34 (23.3 +/- 8.5) than in mice treated with docetaxel only (14.6 +/- 10.1). In short, we have established an optimal treatment schedule for the combination of C34 and chemotherapy that showed synergistic anti-tumor efficacy. We also demonstrated that C34 could increase the number of CD8+ T cells in the tumor microenvironment in mice receiving chemotherapy. These results indicate that combination of C34 and chemotherapy administered with an optimal treatment schedule might have synergistic therapeutic efficacy for patients with lung cancer and breast cancer. Citation Format: Jung-Tung Hung, Jen-Chien Wu, Tsai-Hsien Hung, Jing-Rong Huang, John Yu, Alice L. Yu. Synergistic effect of phenyl alpha-galactosylceramide C34 and chemotherapy on 4T1-tumor bearing mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2005. doi:10.1158/1538-7445.AM2017-2005

c-MET signaling is implicated in a wide variety of human malignancies. Hepatocyte growth factor (HGF) binding to the proto-oncogenic c-MET receptor lead to activate multiple tyrosine kinase signaling pathway. Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Recently, several reports have indicated that inhibition of c-MET signaling induced apoptosis in a variety of cancer cells and recognized as a novel anticancer therapy approach. Previous study from our laboratory also showed that the higher mRNA expression level of HGF, and its downstream genes including HGF receptor (c-Met) and urokinase (uPA) were detected in drug resistant Dx5-C5 cell compared with parental human uterus sarcoma MES-SA cell line. Furthermore, report indicated that the constitutive expression of P-glycoprotein (P-gp) is involved in the HGF/MET related pathway of MDR-positive human hepatocellular carcinoma cell line. Moreover, MDR1 gene overexpressed leukemia cell line also shown more resistance to tyrosine kinase inhibitor imatinib mesylate. These finding suggested that chemoresistant cancer cells may also develop a similar mechanism to against c-MET inhibitor. Our results shown: when treated both cell cancer lines with c-MET inhibitor PHA665752, we found that compared to parental MES-SA cells, the Dx5-C5 cells with highly expressed P-gp was more resistant to PHA665752, the resistance was also reversed by co-treatment of MDR inhibitor verapamil and PHA665752. In addition, when transfection of c-MET shRNA into Dx5-C5 and MES-SA cell line for 48 hrs, we found that the viability was decreased in the c-MET shRNA transfected Dx5-C5 cell line in a dose dependent manner but not in the MES-SA cell line. In conclusion, our study demonstrated that existence of P-glycoprotein in MDR cell line would attenuate c-MET inhibitor induced cell death and may help us to develop a new strategy for treatment of multiple drug resistance cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1908. doi:1538-7445.AM2012-1908

Multiple drug resistance (MDR) is a major issue to attenuate the effectiveness of chemotherapy to many human malignancies. Despite extensively investigation, MDR inhibitors have been discovered serve side effect. Recently, scientists have reported that proteasome inhibitor, Bertezomib (PS-341), induced apoptosis in a variety of cancer cells and recognized as a novel anticancer therapy approach. Previous study revealed that bertezomib inhibits DNA methyltransferase and led to DNA hypomethylation in myeloid leukemia. Despite its success, some patients are resistant to ongoing proteasome inhibitor treatment. These reports suggested that chemoresistant cell line may develop a novel mechanism to against proteasome inhibitor. To verify the hypothesis, we used human CpG island microarray to indentify epigenetic change and genes expression profile in parental human uterus sarcoma cell line (MES-SA) and MES-SA variant drug resistant cell line (Dx5-C5) Our data has shown that the global genes were hypomethylated in both PS-341 treated MES-SA and Dx5-C5 cell line. Furthermore, the Wnt signalling pathway and cell cycle related gene have significant altered in DNA methylation pattern of Dx5-C5. In summary, our study demonstrated that the cell cycle related gene(s) and upstream gene(s) of Wnt pathway altered its DNA methylation pattern and mRNA expression level in MDR cell line. These data may help us to develop a new strategy for treatment of multiple drug resistance cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4914.