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- Title
Interplay Between Autophagy And Apoptosis In A Pancreatic Cancer Cell Line Treated With SRJ23, Gemcitabine Or Combination Of Both Agents.
- Authors
Selvarajoo, Nityaa; Sagineedu, Sreenivasa Rao; Woei Lim, Jonathan Chee; Kok Lian Ho; Stanslas, Johnson
- Abstract
Introduction: Pancreatic cancer is an aggressive disease. Although its occurrence rate remains low in Malaysia, it is the third leading cause of cancer-related death in the USA because of limited treatment options. Gemcitabine is a standard chemotherapy for pancreatic cancer. Most pancreatic cancers harbour K-Ras mutations that lead to constitutive activation of mitogen-activated protein kinase (MAPK) signalling pathway. The aim of this study was to explore the potential of Ras inhibitor, SRJ23 in modulating autophagy and apoptosis in a pancreatic cancer cell line, Capan-2 alone or in combination with gemcitabine. Methods: 3-(4,5-Dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used in assessing the growth inhibition of SRJ23 alone or in combination with gemcitabine at a concentration of 0.1-100 μM for 96 hr against Capan-2 cells. Compusyn software was used to determine the combination index of SRJ23 and gemcitabine drug combination treatment. Immunoblotting assay was used to detect the expression of autophagy markers (LC3, Beclin-1, ATG5) and apoptosis markers (Bax, Bcl-2, caspase-3 and cleaved caspase-3). Additionally, MDC staining was used to detect the change of autophagy at morphological level. Results: Combination of 10 μM SRJ23 with 10μM gemcitabine showed synergistic growth inhibitory effect with combination index of 0.87. Furthermore, SRJ23 or gemcitabine treatment alone induced autophagy by increasing the protein expression of autophagy marker, LC3B-II and it further elevated the autophagy protein level when treated in combination. Simultaneously, SRJ23 and gemcitabine combination treatment significantly increased the protein expression of apoptotic marker, cleaved caspase-3 compared to its single treatment. MDC staining showed that the fluorescent density was higher and the number of MDC-labelled particles in Capan-2 cells was greater in the SRJ23 and gemcitabine combination treatment compared to the single treatments. Conclusion: The findings suggested that combination treatment of SRJ23 and gemcitabine was indeed beneficial in regulating autophagy to promote apoptosis of Capan-2 cells.
- Subjects
MALAYSIA; PANCREATIC cancer; AUTOPHAGY; CANCER cells; MITOGEN-activated protein kinases; GEMCITABINE; PANCREATIC tumors
- Publication
Malaysian Journal of Medicine & Health Sciences, 2022, Vol 18, p27
- ISSN
1675-8544
- Publication type
Article