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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Simple Summary

Failure of chemotherapy is common during the treatment of colon cancer, and there is a compelling need to develop alternative therapeutic approaches against this common malignancy. Metformin, which is an oral hypoglycaemic agent used for treating diabetes mellitus, and vitamin D have shown promising anticancer activities, and both agents boosted the actions of chemotherapy against colon cancer. This study, therefore, measured the potential beneficial effects of adding metformin and/or active vitamin D to the main cytotoxic drug used for treating colon cancer. The results demonstrate that metformin had superior anticancer effects relative to active vitamin D and ameliorated the effects of chemotherapy in animals and in cells. To the best of our knowledge, this study is also the first to report that triple treatment with the drugs of interest showed the best inhibition of cancer progression, which could provide a better therapeutic strategy against colon cancer.

Abstract

Chemoresistance to 5-fluorouracil (5-FU) is common during colorectal cancer (CRC) treatment. This study measured the chemotherapeutic effects of 5-FU, active vitamin D3 (VD3), and/or metformin single/dual/triple regimens as complementary/alternative therapies. Ninety male mice were divided into: negative and positive (PC) controls, and 5-FU, VD3, Met, 5-FU/VD3, 5-FU/Met, VD3/Met, and 5-FU/VD3/Met groups. Treatments lasted four weeks following CRC induction by azoxymethane. Similar regimens were also applied in the SW480 and SW620 CRC cell lines. The PC mice had abundant tumours, markedly elevated proliferation markers (survivin/CCND1) and PI3K/Akt/mTOR, and reduced p21/PTEN/cytochrome C/caspase-3 and apoptosis. All therapies reduced tumour numbers, with 5-FU/VD3/Met being the most efficacious regimen. All protocols decreased cell proliferation markers, inhibited PI3K/Akt/mTOR molecules, and increased proapoptotic molecules with an apoptosis index, and 5-FU/VD3/Met revealed the strongest effects. In vitro, all therapies equally induced G1 phase arrest in SW480 cells, whereas metformin-alone showed maximal SW620 cell numbers in the G0/G1 phase. 5-FU/Met co-therapy also showed the highest apoptotic SW480 cell numbers (13%), whilst 5-FU/VD3/Met disclosed the lowest viable SW620 cell percentages (81%). Moreover, 5-FU/VD3/Met revealed maximal inhibitions of cell cycle inducers (CCND1/CCND3), cell survival (BCL2), and the PI3K/Akt/mTOR molecules alongside the highest expression of cell cycle inhibitors (p21/p27), proapoptotic markers (BAX/cytochrome C/caspase-3), and PTEN in both cell lines. In conclusion, metformin monotherapy was superior to VD3, whereas the 5-FU/Met protocol showed better anticancer effects relative to the other dual therapies. However, the 5-FU/VD3/Met approach displayed the best in vivo and in vitro tumoricidal effects related to cell cycle arrest and apoptosis, justifiably by enhanced modulations of the PI3K/PTEN/Akt/mTOR pathway.

Details

Title
In Vivo and In Vitro Enhanced Tumoricidal Effects of Metformin, Active Vitamin D3, and 5-Fluorouracil Triple Therapy against Colon Cancer by Modulating the PI3K/Akt/PTEN/mTOR Network
Author
Almaimani, Riyad Adnan 1   VIAFID ORCID Logo  ; Aslam, Akhmed 2   VIAFID ORCID Logo  ; Ahmad, Jawwad 2 ; Mahmoud Zaki El-Readi 3   VIAFID ORCID Logo  ; El-Boshy, Mohamed E 4   VIAFID ORCID Logo  ; Abdelghany, Abdelghany H 5   VIAFID ORCID Logo  ; Idris, Shakir 2 ; Alhadrami, Mai 6 ; Althubiti, Mohammad 1 ; Almasmoum, Hussain A 2   VIAFID ORCID Logo  ; Ghaith, Mazen M 2 ; Elzubeir, Mohamed E 1 ; Safaa Yehia Eid 1 ; Refaat, Bassem 2   VIAFID ORCID Logo 

 Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia; [email protected] (R.A.A.); [email protected] (M.Z.E.-R.); [email protected] (M.A.); [email protected] (M.E.E.); [email protected] (S.Y.E.) 
 Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; [email protected] (A.A.); [email protected] (J.A.); [email protected] (M.E.E.-B.); [email protected] (A.H.A.); [email protected] (S.I.); [email protected] (H.A.A.); [email protected] (M.M.G.) 
 Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia; [email protected] (R.A.A.); [email protected] (M.Z.E.-R.); [email protected] (M.A.); [email protected] (M.E.E.); [email protected] (S.Y.E.); Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assuit 71524, Egypt 
 Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; [email protected] (A.A.); [email protected] (J.A.); [email protected] (M.E.E.-B.); [email protected] (A.H.A.); [email protected] (S.I.); [email protected] (H.A.A.); [email protected] (M.M.G.); Clinical Pathology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt 
 Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; [email protected] (A.A.); [email protected] (J.A.); [email protected] (M.E.E.-B.); [email protected] (A.H.A.); [email protected] (S.I.); [email protected] (H.A.A.); [email protected] (M.M.G.); Department of Anatomy, Faculty of Medicine, Alexandria University, Alexandria 21544, Egypt 
 Department of Pathology, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia; [email protected] 
First page
1538
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2642362776
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.