Although the combination of gemcitabine with a variety of cytotoxic and targeted agents has generally shown no significant survival advantage as compared with gemcitabine alone, still, many targeted agents against various pathways remain to be tested in pancreatic cancer. Previously, we have observed that the combined treatment with TRAIL plus shRNA of HSP27 induced complete cell death in MiaPaCa-2 pancreatic cell. Here three different targets were invited with TRAIL for chemotherapy combination with gemcitabine using three pancreatic cancer cell lines. We observed that TRAIL treatment to all three pancreatic cells have relieved gemcitabine-induced resistance. More importantly, three different pancreatic cancer cell lines showed their own unique differential sensitivities to targeted agents examined. For example, in case of MiaPaCa-2, gemcitabine/TRAIL/shRNA of survivin was more effective to cell death than HPAC, whereas TRAIL plus downregulation of survival-related molecules (survivin, XIAP, Bcl-xL) effectively enhanced cell death of Panc-1 even without gemcitabine. Then, we extended the survival-related molecules to upstreams such as Src, PI3K-Akt, or NF-κB and inhibited their downstream signals using PP2, wortmannin, SN50, respectively. From their results, TRAIL plus SN50 decreased NF-κB activation and concomitant significant cell death in MiaPaCa-2 which has an acquired resistance of NF-κB after gemcitabine. Based on this result, it was found that combination of gemcitabine/TRAIL/SN50 dramatically increased cell death of MiaPaCa-2, whereas in case of Panc-1 or HPAC, gemcitabine/TRAIL/PP2 dramatically increased cell death. Taken all together, a better knowledge of the multiple molecular pathways implicated in pancreatic carcinogenesis should be much more specifically considered to control the various gemcitabine-resistant pancreatic cancer cells.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C237.
Citation Format: Seungha Lee, So Y. Kim, Dongxu Kang, Hye J. Choi, Joo-Hang Kim, Jae Jin Song. Overcoming gemcitabine resistance with TRAIL plus enhancer of anti-survival potential in pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C237.