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.
항암치료 요법은 크게 방사선치료, 외과적 수술 및 화학요법 세가지로 분류된다. 항암화학요법은 가장 효과적인 암 치료 방법 중 하나로 알려져 있으나 암세포의 유전적 다양성 또는 지속적인 항암제 투여로 인한 암세포의 약물 내성은 항암화학요법의 실패를 초래하는 주요 원인 중 하나이다. 그에 따라 전세계적으로 항암제 내성으로 인한 치료 실패율을 낮추기 위해 두 가지 이상의 약물을 이용해 환자를 치료하는 약물 병합치료에 대한 연구가 많이 이루어지고 있다. 본 연구에서는 단순한 가산 효과가 아닌 시너지적인 효과를 유도하여 항암 효능을 극대화 시킬 수 있는 약물 조합에 대한 연구를 진행하였다. 악성뇌교종 및 유방암에서 선천적 또는 후천적으로 발생하는 약물 저항성 신호 기전을 밝히고, 이 기전들을 바탕으로 하여 암세포 사멸을 증가시킬 수 있는 시너지적인 약물 조합을 발굴하였다. 본 연구는 나아가 암세포의 특성에 따른 약물에 대한 민감도를 예측하고, 특정 약물에 대한 민감도를 높일 수 있는 조합의 약물을 병합 처리함으로써 약물 저항성을 갖는 암의 치료 효율을 높이는 데 활용할 수 있을 것이다.
