Synergistic antitumor effect of 5-fluorouracil and withaferin-A induces endoplasmic reticulum stress-mediated autophagy and apoptosis in colorectal cancer cells
| dc.contributor.author | Alnuqaydan, Abdullah | |
| dc.contributor.author | Almutary, Abdulmajeed | |
| dc.contributor.author | Rah, Bilal | |
| dc.contributor.author | Singh Chauhan, Shailender | |
| dc.date.accessioned | 2024-11-13T08:02:10Z | |
| dc.date.available | 2024-11-13T08:02:10Z | |
| dc.date.issued | 2020 | |
| dc.description | Colorectal cancer (CRC) is one of the most common gastrointestinal cancers with a relatively high mortality rate [1]. Contemporary, surgical measures are the primary option followed by chemotherapy in the CRC [2]. However, in spite of incredible advancement in treatment methodologies, the therapeutic outcome is insignificant due to acquired resistance and deleterious effects. The first line of therapy against CRC is 5-fluorouracil (5-FU) which persuades antitumor potential by mitigating the thymidylate synthase (TS) activity and reduces the synthesis of DNA and RNA [3]. Although 5-FU has established its survival benefits quite astonishingly, the applications in clinical settings have been significantly limited due to the development of drug resistance plus adverse side effects at higher doses [4]. | |
| dc.description.abstract | The development of chemo-resistance against 5-fluorouracil (5-FU) in tumor cells is one of the main debacles in colorectal cancer (CRC) patients. A recent combination of 5-FU with oxaliplatin or cetuximab drastically improves the survival rate in CRC patients; however, the toxicity issue cannot be evaded completely. Thus, searching for novel drug combinations with high specificity and low toxicity is seemingly important. Owing to the less undesirable effects of natural products on normal cells, here we investigated the synergistic antitumor effect of withaferin-A (WA) in combination with 5-FU. Our results demonstrate that the combination of WA and 5-FU induces a significant antiproliferative effect and modulates endoplasmic reticulum (ER) stress in favor of cell death in colorectal cancer (CRC) cells. Mechanistically, the combination upregulates the expression of ER stress sensors (BiP, PERK, CHOP, ATF-4, and eIF2α) and executes PERK axis mediated apoptosis in CRC cells. Additionally, the combined treatment of WA and 5-FU mediated ER stress induces autophagy and apoptosis, which were confirmed by immunoblotting, acridine orange (AO) staining and annexin-V FITC by flow cytometry. In contrast, inhibition of ER stress with salubrinal significantly decreases both autophagic and apoptotic cell populations. Moreover, pharmacological inhibition of either autophagy or apoptosis by their respective inhibitors 3-methyladenine (3-MA) or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoro-methyl ketone (Z-VAD-FMK) decreases their respective population of cells but could not affect either of the population significantly. Finally, the combination attenuates the expression of β-catenin pathway associated proteins and arrests cell cycle at the G2M phase in CRC cells. In summary, the combination of WA and 5-FU decreases cell viability by inducing ER stress-mediated induction of autophagy and apoptosis, inhibiting the β-catenin pathway and arresting the cell cycle at a G2M phase in CRC cells. Keywords: Synergistic effect, endoplasmic reticulum, autophagy, apoptosis, colorectal cancer | |
| dc.identifier.citation | Alnuqaydan, A. M., Rah, B., Almutary, A. G., & Chauhan, S. S. (2020). Synergistic antitumor effect of 5-fluorouracil and withaferin-A induces endoplasmic reticulum stress-mediated autophagy and apoptosis in colorectal cancer cells. American Journal of Cancer Research, 10(3), 799. | |
| dc.identifier.uri | https://repository.adu.ac.ae/handle/1/7013 | |
| dc.language.iso | en | |
| dc.publisher | e-Century Publishing Corporation | |
| dc.title | Synergistic antitumor effect of 5-fluorouracil and withaferin-A induces endoplasmic reticulum stress-mediated autophagy and apoptosis in colorectal cancer cells | |
| dc.type | Article |