Cancer and diabetes: the interlinking metabolic pathways and repurposing actions of antidiabetic drugs

Abstract

Cancers are regarded as one of the main causes of death and result in high health burden worldwide. The management of cancer include chemotherapy, surgery and radiotherapy. The chemotherapy, which involves the use of chemical agents with cytotoxic actions is utilised as a single treatment or combined treatment. However, these managements of cancer such as chemotherapy poses some setbacks such as cytotoxicity on normal cells and the problem of anticancer drug resistance. Therefore, the use of other therapeutic agents such as antidiabetic drugs is one of the alternative interventions used in addressing some of the limitations in the use of anticancer agents. Antidiabetic drugs such as sulfonylureas, biguanides and thiazolidinediones showed beneficial and repurposing actions in the management of cancer, thus, the activities of these drugs against cancer is attributed to some of the metabolic links between the two disorders and these includes hyperglycaemia, hyperinsulinemia, inflammation, and oxidative stress as well as obesity. Furthermore, some studies showed that the use of antidiabetic drugs could serve as risk factors for the development of cancerous cells particularly pancreatic cancer. However, the beneficial role of these chemical agents overweighs their detrimental actions in cancer management. Hence, the present review indicates the metabolic links between cancer and diabetes and the mechanistic actions of antidiabetic drugs in the management of cancers.

Keywords: Anticancer drugs; Antidiabetic drugs; Cancer; Diabetes; Repurposing action.

Fig. 1

General structure of sulfonylureas, indicating S-aryl sulfonylurea, para-moiety on the phenyl ring (R1), and other substituents at N′ end terminating the urea (R2)

Fig. 2

Chemical structures of some sulfonylureas

Fig. 3

Schematic representation of anticancer and antidiabetic mechanism of sulfonylureas (SU). The binding of SU with sulphonylurea receptor (SUR) inhibits the efflux of K⁺, activates the influx of Ca²⁺ and induces the generation of reactive oxygen species (ROS). The accumulation of reactive oxygen species in turn results into apoptosis whereas increased influx of calcium (II) ions causes exocytosis of insulin by rearrangement of cytoskeleton. ATP adenosine triphosphate, ADP adenosine diphosphate

Fig. 4

General structure of a biguanide

Fig. 5

Structures of some biguanides

Fig. 6

Antitumor action of metformin. The drug could inhibit the tumor cell proliferation by various mechanisms; A by ceasing the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway, B by blocking the activity of complex I of the oxidative phosphorylation, C by interrupting the Kreb’s cycle pathway through carboxylation of α-ketoglutarate, thus inhibiting the pathway for lipogenic citrate synthesis, D by enhancing apoptosis via targeting AMPK and mTOR pathways or via targeting STAT-3 pathway either directly or through AMPK. LKB-1 liver kinase B-1, AMP adenosine monophosphate

Fig. 7

Structure of thiazolidinedione

Fig. 8

Structure of some thiazolidinediones

Fig. 9

Antitumor mechanism of Thiazolidinediones (TZDs). These drugs inhibit the proliferation of tumor cells either through peroxisome-proliferator-activated receptor gamma (PPARγ)-dependent or PPARγ-independent mechanisms. In PPARγ-dependent mechanism, the activation of PPARγ receptor by these drugs switch on the transcription of various target genes which in turn help in suppressing the growth of tumor. In PPARγ- independent mechanisms TZDs blocks the mTOR pathway by activation of AMPK), inhibits the expression of prostaglandin E2 (PGE2) receptor and vascular endothelial growth factor (VEGF) genes as well as induction of cyclins degradation. AMP adenosine monophosphate