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Lercanidipine 처리시 프로테아좀 억제제의 암세포 사멸을 증대시키는 paraptosis 세포 사멸 기전 연구
- Author(s)
- 이아름
- Advisor
- 최경숙
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2019-08
- Language
- eng
- Alternative Abstract
- Bortezomib (Btz), a proteasome inhibitor (PI), is effective in treating multiple myeloma and mantle cell lymphoma, but its anticancer effects are not satisfactory in solid tumors. In this study, we examined the possibility that the sensitivity to PIs can be enhanced by drug repositioning. We first show that lercanidipine (Ler), an antihypertensive agent, increases the cytotoxicity of various PIs including Btz, carfilzomib (Cfz), and ixazomib (Ixz) by inducing paraptosis-associated cell death, which is accompanied by severe dilation of mitochondria and the endoplasmic reticulum (ER) and in many solid tumor cell lines. We have found that mitochondrial Ca2+ overload induced by the combination of Btz and Ler is crucial for mitochondrial vauolation and subsequent mitochondrial membrane potential loss in MDA-MB 435S cells. In addition, Ler enhances Btz-mediated ER stress due to accumulation of misfolded proteins, contributing to ER vacuolization. Taken together, our results suggest that the combined regimen of PIs and Ler can effectively kill cancer cells through structural and functional disturbance in mitochondria and the ER.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 4. Theses(Ph.D)
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