غلبه استفاده از ملاتونین بر مقاومت دارو در شیمی درمانی سرطان Does the use of melatonin overcome drug resistance in cancer chemotherapy?

1. Introduction The human body encloses trillions of DNA carrying cells. The DNA instructs the cells to divide and differentiate. Under physiologic conditions, division and differentiation are organized and well-regulated processes; however, should unsolicited mutations strike the vital regions of the DNA encoding regulatory genes, the instructions of harnessed proliferation and differentiation become derailed, leading to an aberrant proliferation of cells, which ultimately gives rise to the development of cancer. In some cases, early detection enables surgical removal of tumors. However, other therapeutic measures such as radiotherapy, chemotherapy as well as novel targeted therapies are generally reserved for disseminating aggressive and metastatic cancers, generally considered as the cornerstones of cancer therapy. Since the adoption of these therapeutic measures, they have evolved into curative options for some cancers. Unfortunately, however, two obstacles have impeded the achievement of a successful treatment, granting complete remission: (i) adverse toxicities in the healthy cells and tissues (offtarget hits) and (ii) development of resistance to chemo/radiotherapy. In general, the resistance of cancer cells can be categorized into intrinsic resistance and acquired resistance. Almost half of all cancer cases are resistant to chemotherapy per se, while the majority of the remaining acquires resistance at some point along the treatment course [1]. Genomic instability is a well-recognized trait of all cancer cells. This instability is typically consequent to damages to the DNA repair system, impaired checkpoints of DNA damage such as the p53 tumor suppressor gene, deflected cell cycle checkpoints, and increased loss of telomeres [2]. Keeping in mind that an individual tumor can approximately host 109 –1012 cells with possibly 105 mutants, cultivation of a highly heterogeneous population within one tumor is expected to occur. Variations in the patterns of mutations and epigenetic modifications in oncogenes, tumor suppressor genes and genes related to the development of drug resistance result in the expression of different resistance components and the down-regulation of elements conferring sensitivity to external insults [3]. With the presence of multiple clones within a tumor, cytotoxic therapies such as chemo/radiotherapy fabricate an evolutionary process of selection, favoring the survival of the fittest resistant clones and their rapid expansion [4]. To impede the propagation of resistant clones, a successful treatment must be capable of abating the resistance mechanisms as well as sensitizing the non-resistant cancer cells to cytotoxic therapy. Overcoming such a resistance can be achieved through the designing of novel multifunctional agents or by the co-administration of compounds with sensitizing functions. Undoubtedly, it is advantageous to select a compound with additional benefits such as (i) selective cytotoxicity on cancer cells, sparing the healthy cells and tissues, (ii) protection of healthy cells against chemo/ radiotherapy toxicity, (iii) improving the patient’s overall condition, and (iv) increasing the patient’s quality of life and extending posttreatment survival. The extracted data from articles were included and summarized in Table 1.