Investigation of resistance mechanism and synergistic drug combination to improve treatment efficiency of drug resistant solid cancers

Abstract

Though a chemotherapy is the most effective anti-cancer therapy, a drug resistance is the biggest obstacle leading a failure of anti-cancer therapy. Therefore, there have been many efforts to study combinational therapy for diagnosis and treatment of drug resistance by increasing the therapy efficiency. After general introduction of chemo-resistance and combination therapy in chapter 1, I will elucidate the research about the synergistic anti-cancer effect of $\gamma$-secretase inhibitor (GSI) and temozolomide (TMZ) in glioblastoma multiforme (GBM), a malignant brain tumor with poor prognosis, in chapter 2. One of the important characteristics of solid cancers is a highly dense environment due to infinite cell proliferation. I investigated the effect of cell to cell contact on malignant characteristics of cancer cells. In high confluency, GBM cells became resistant to TMZ, and cell viabilities of various solid cancer cell lines were increased. Notch-1 intracellular domain (NICD) was increased in high density-cultured cells, and the inhibition of NICD by GSI restricted the density-dependent malignant changes. Interestingly, hypoxia inducible factor-1$\alpha$ (HIF-1$\alpha$) was also elevated in highly confluent cells along with the NICD. Direct binding of NICD stimulated HIF-1$\alpha$ translocation into nucleus, and they functioned as transcription factors. Taken together, I suggested that the combined treatment of GSI could be a novel and powerful therapeutic strategy against chemo-resistant cancers. Another major feature of malignant cancer is angiogenesis. In chapter 3, I studied about the efficient drug combination of anti-angiogenesis drug and chemotherapeutic drug on GBM. Combined treatment of VEGFR2 inhibitor (SU1498) and TMZ showed synergistic anti-cancer effect on four GBM cell lines

U251-MG, U373-MG, CRT-MG and LN215-MG. The protein and mRNA level of neuropilin-1 (NRP-1), a co-receptor of VEGFR2, were decreased after TMZ treatment. Moreover, NRP-1 downregulation by siRNA transfection sensitized GBM cells to SU1498. Consequently, I suggested the TMZ treatment augments SU1498-mediated cell death of GBM. In the last chapter 4, I validated a synthetic lethality of ginsenoside (compound-K (C-K) and protopanaxadiol (PPD)) and doxorubicin in vivo using breast cancer xenograft model. The C-K or PPD stimulated cytotoxicity of doxorubicin by sensitizing MCF-7 cells to apoptotic stimulus via mitochondrial fragmentation. Conclusively, I examined novel signaling pathways of drug resistance in solid cancers, and further suggested drug combinations that induce synergistic anti-cancer effect based on the resistance mechanism.