2. Academic Validation
  3. 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

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

  • Cancers (Basel). 2022 Mar 17;14(6):1538. doi: 10.3390/cancers14061538.
Riyad Adnan Almaimani 1,  Akhmed Aslam 2,  Jawwad Ahmad 2,  Mahmoud Zaki El-Readi 1 3,  Mohamed E El-Boshy 2 4,  Abdelghany H Abdelghany 2 5,  Shakir Idris 2,  Mai Alhadrami 6,  Mohammad Althubiti 1,  Hussain A Almasmoum 2,  Mazen M Ghaith 2,  Mohamed E Elzubeir 1,  Safaa Yehia Eid 1,  Bassem Refaat 2
Affiliations

Affiliations

  • 1 Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia.
  • 2 Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia.
  • 3 Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assuit 71524, Egypt.
  • 4 Clinical Pathology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt.
  • 5 Department of Anatomy, Faculty of Medicine, Alexandria University, Alexandria 21544, Egypt.
  • 6 Department of Pathology, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia.
PMID: 35326689 DOI: 10.3390/cancers14061538
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.

Keywords

apoptosis; calcitriol; cell cycle; chemoresistance; mammalian target of rapamycin; metformin; phosphatidylinositol-3-kinase; protein kinase B.

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