Wortmannin Inhibits Cell Growth and Induces Apoptosis in Colorectal Cancer Cells by Suppressing the PI3K/AKT Pathway

Nastaran Bani; Farzad Rahmani; Neda Shakour; Forouzan Amerizadeh; Ghazaleh Khalili-Tanha; Majid Khazaei; Seyed Mahdi Hassanian; Mohammad Amin Kerachian; Mohammad Reza Abbaszadegan; Majid Mojarad; Farzin Hadizadeh; Gordon A Ferns; Amir Avan

doi:10.2174/0118715206296355240325113920

Wortmannin Inhibits Cell Growth and Induces Apoptosis in Colorectal Cancer Cells by Suppressing the PI3K/AKT Pathway

Anticancer Agents Med Chem. 2024 Apr 4. doi: 10.2174/0118715206296355240325113920. Online ahead of print.

Authors

Nastaran Bani^{1

2

3}, Farzad Rahmani⁴, Neda Shakour^{5

6}, Forouzan Amerizadeh^{1

2}, Ghazaleh Khalili-Tanha^{1

2}, Majid Khazaei², Seyed Mahdi Hassanian², Mohammad Amin Kerachian^{1

3

3}, Mohammad Reza Abbaszadegan^{1

3}, Majid Mojarad^{1

3}, Farzin Hadizadeh^{7

5}, Gordon A Ferns⁸, Amir Avan^{1

2

3}

Affiliations

¹ Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
² Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
³ Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁴ Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁵ Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
⁶ Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.
⁷ Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
⁸ Brighton & Sussex Medical School, Department of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK.

PMID: 38584531
DOI: 10.2174/0118715206296355240325113920

Abstract

Background: Colorectal cancer (CRC) remains a significant contributor to mortality, often exacerbated by metastasis and chemoresistance. Novel therapeutic strategies are imperative to enhance current treatments. The dysregulation of the PI3K/Akt signaling pathway is implicated in CRC progression. This study investigates the therapeutic potential of Wortmannin, combined with 5-fluorouracil (5-FU), to target the PI3K/Akt pathway in CRC.

Methods: Anti-migratory and antiproliferative effects were assessed through wound healing and MTT assays. Apoptosis and cell cycle alterations were evaluated using Annexin V/Propidium Iodide Apoptosis Assay. Wortmannin's impact on the oxidant/antioxidant equilibrium was examined via ROS, SOD, CAT, MDA, and T-SH levels. Downstream target genes of the PI3K/AKT pathway were analyzed at mRNA and protein levels using RTPCR and western blot, respectively.

Results: Wortmannin demonstrated a significant inhibitory effect on cell proliferation, modulating survivin, cyclinD1, PI3K, and p-Akt. The PI3K inhibitor attenuated migratory activity, inducing E-cadherin expression. Combined Wortmannin with 5-FU induced apoptosis, increasing cells in sub-G1 via elevated ROS levels.

Conclusion: This study underscores Wortmannin's potential in inhibiting CRC cell growth and migration through PI3K/Akt pathway modulation. It also highlights its candidacy for further investigation as a promising therapeutic option in colorectal cancer treatment.

Keywords: 5-FU.; Colorectal cancer; PI3K/Akt pathway; antitumor effects; wortmannin.