AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma

Eslam E Abd El-Fattah; Sameh Saber; Mahmoud E Youssef; Hanan Eissa; Eman El-Ahwany; Noha A Amin; Mohammed Alqarni; Gaber El-Saber Batiha; Ahmad J Obaidullah; Mohamed M Y Kaddah; Ahmed Gaafar Ahmed Gaafar; Ahmed A E Mourad; Gomaa Mostafa-Hedeab; Amir Mohamed Abdelhamid

doi:10.3389/fphar.2021.720173

AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma

Front Pharmacol. 2022 Jan 12:12:720173. doi: 10.3389/fphar.2021.720173. eCollection 2021.

Authors

Eslam E Abd El-Fattah¹, Sameh Saber², Mahmoud E Youssef², Hanan Eissa³, Eman El-Ahwany⁴, Noha A Amin⁵, Mohammed Alqarni⁶, Gaber El-Saber Batiha⁷, Ahmad J Obaidullah^{8

9}, Mohamed M Y Kaddah¹⁰, Ahmed Gaafar Ahmed Gaafar¹¹, Ahmed A E Mourad¹¹, Gomaa Mostafa-Hedeab^{12

13}, Amir Mohamed Abdelhamid²

Affiliations

¹ Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
² Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
³ Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
⁴ Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt.
⁵ Department of Hematology, Theodor Bilharz Research Institute, Giza, Egypt.
⁶ Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia.
⁷ Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
⁸ Drug Exploration and Development Chair (DEDC), Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
¹⁰ Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications, New Borg El-Arab, Egypt.
¹¹ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
¹² Pharmacology Department and Health Research Unit, Medical College, Jouf University, Jouf, Saudi Arabia.
¹³ Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt.

Abstract

HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.

Keywords: AMPKα; Akt; HIF-1α; MAPK; angiogenesis; hepatocellular carcinoma; mTOR; sitagliptin.