Melatonin as a regulator of apoptosis in leukaemia: molecular mechanism and therapeutic perspectives

Abstract

Leukaemia is a dangerous malignancy that causes thousands of deaths every year throughout the world. The rate of morbidity and mortality is significant despite many advancements in therapy strategies for affected individuals. Most antitumour medications used now in clinical oncology use apoptotic signalling pathways to induce cancer cell death. Accumulated data have shown a direct correlation between inducing apoptosis in cancer cells with higher tumour regression and survival. Until now, the efficacy of melatonin as a powerful antitumour agent has been firmly established. A change in melatonin concentrations has been reported in multiple tumours such as endometrial, hematopoietic, and breast cancers. Findings show that melatonin's anticancer properties, such as its prooxidation function and ability to promote apoptosis, indicate the possibility of utilizing this natural substance as a promising agent in innovative cancer therapy approaches. Melatonin stimulates cell apoptosis via the regulation of many apoptosis facilitators, including mitochondria, cytochrome c, Bcl-2, production of reactive oxygen species, and apoptosis receptors. This paper aimed to further assess the anticancer effects of melatonin through the apoptotic pathway, considering the role that cellular apoptosis plays in the pathogenesis of cancer. The effect of melatonin may mean that it is appropriate for use as an adjuvant, along with other therapeutic approaches such as radiotherapy and chemotherapy.

Keywords: apoptosis; leukaemia; melatonin; signalling pathway; therapy.

FIGURE 1

Schema of intrinsic and extrinsic pathways of apoptosis. The extrinsic pathway starts with the stimulation of death receptors followed by activation of caspase-8 and -10. The intrinsic pathway initiates in response to cell damage and continues by activation of caspase-9. Both pathways join in caspase-3 activation, which results in apoptosis.

FIGURE 2

Induction of apoptosis in leukaemia by melatonin. Melatonin can induce apoptosis in leukaemic cells by inducing ROS formation. In addition, melatonin can downregulate the expression of Cox-2 and hTERT genes, which leads to hindering the inhibitory effect of these two proteins on the caspase-dependent pathway of apoptosis. The combination therapy of melatonin with antitumour drugs in leukaemia can synergize the induction of apoptosis in tumoral cells. Each pathway modulates the function of proteins in the waterfall of apoptosis.