PMID- 32266092
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 2156-6976 (Print)
IS  - 2156-6976 (Electronic)
IS  - 2156-6976 (Linking)
VI  - 10
IP  - 3
DP  - 2020
TI  - Synergistic antitumor effect of 5-fluorouracil and withaferin-A induces 
      endoplasmic reticulum stress-mediated autophagy and apoptosis in colorectal 
      cancer cells.
PG  - 799-815
AB  - 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 eIF2alpha) 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 
      beta-catenin pathway associated proteins and arrests cell cycle at the G(2)M 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 beta-catenin pathway and arresting the cell cycle at a G(2)M phase in CRC cells.
CI  - AJCR Copyright (c) 2020.
FAU - Alnuqaydan, Abdullah M
AU  - Alnuqaydan AM
AD  - Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim 
      University Saudi Arabia.
FAU - Rah, Bilal
AU  - Rah B
AD  - Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim 
      University Saudi Arabia.
FAU - Almutary, Abdulmajeed G
AU  - Almutary AG
AD  - Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim 
      University Saudi Arabia.
FAU - Chauhan, Shailender Singh
AU  - Chauhan SS
AD  - Department of Cellular and Molecular Medicine, University of Arizona Tucson, 
      Arizona, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20200301
PL  - United States
TA  - Am J Cancer Res
JT  - American journal of cancer research
JID - 101549944
PMC - PMC7136917
OTO - NOTNLM
OT  - Synergistic effect
OT  - apoptosis
OT  - autophagy
OT  - colorectal cancer
OT  - endoplasmic reticulum
COIS- None.
EDAT- 2020/04/09 06:00
MHDA- 2020/04/09 06:01
PMCR- 2020/03/01
CRDT- 2020/04/09 06:00
PHST- 2019/12/16 00:00 [received]
PHST- 2020/02/11 00:00 [accepted]
PHST- 2020/04/09 06:00 [entrez]
PHST- 2020/04/09 06:00 [pubmed]
PHST- 2020/04/09 06:01 [medline]
PHST- 2020/03/01 00:00 [pmc-release]
PST - epublish
SO  - Am J Cancer Res. 2020 Mar 1;10(3):799-815. eCollection 2020.