Melatonin as an adjuvant treatment modality with doxorubicin
Introduction
Treatment modalities based on combination chemotherapies have attracted the attention of researchers/clinicians due to their potential in improving the outcome of patients with a variety of different cancers [1,2]. In general, different drugs used in chemotherapy have non-overlapping mechanisms which provide enhanced antitumor effects while minimizing drug resistance. Despite the advances in this field, some of these chemotherapeutic regimens may increase the toxicity in patients without any changes in the beneficial effects over single drug treatment [3,4]. Currently, combinations of antitumor drugs are being tested in vitro prior to in vivo investigations and some parameters (such as combination index and IC50) are used to determine their success [[5], [6], [7]]. However, these parameters may not be sufficient for successful translation of these regimens to either the in vivo or clinical situation [8]. Many studies have shown that melatonin (MLT) exerts several antitumor effects, including suppressing cancer cell proliferation, as well as reducing cell cycle progression, invasion, and metastasis in addition to inducing cancer cell apoptosis [[9], [10], [11], [12], [13], [14]]. Moreover, MLT is an endogenous molecule of pineal origin that reduces the adverse effects, e.g., dermatitis, intestinal injury, and cardiotoxicity, of a variety of drugs [[15], [16], [17], [18]]. Herein, we review the outcome studies that indicate MLT may serve as a potential adjuvant in Dox-based chemotherapies by increasing antitumor effects of chemotherapeutic drugs and/or reducing their adverse effects.
Section snippets
What is MLT?
MLT, N-acetyl-5-methoxytryptamine, after its discovery in 1958 was initially implicated in circadian and circannial rhythm regulation [19]. This ubiquitous molecule is present through the animal and plant kingdoms and is possibly present in all tissues [20]. In unicell organisms such bacteria, MLT production is necessary for decreasing the effects of oxidizing environments on the organism [21]. In multicellular organisms, all cells are potentially capable of producing MLT in their mitochondria
Doxorubicin as a chemotherapeutic drug
In the 1950s, a novel strain of Streptomyces peucetius was isolated to develop a new antibiotic identified as daunorubicin [31,32]. This compound was found to exert antitumor activities in mice. However, in 1967 daunorubicin was recognized as a fatal agent that caused cardiac toxicity. By genetic manipulating the Streptomyces spp., a new agent named adriamycin was developed which later became known as doxorubicin (Dox). Despite the higher therapeutic index of Dox compared to its other
MLT enhances the antitumor effects of dox
While the majority of studies on the role of MLT as an adjuvant in Dox therapy have focused on MLT's ability to reduce the toxic effects of Dox, several have shown that MLT can also promote antitumor effects with Dox, e.g., by inducing apoptosis and suppressing metastasis. Tran and colleagues [41] reported that in breast cancer MLT exerts a synergistic effect with Dox for inducing apoptosis. They showed that the apoptosis induction occurs through reducing AMP-activated protein kinase α1 (AMPK
Cardiotoxicity
Cardiac damage is the most critical side effect of the application of anthracycline cytostatic drugs like DOX in cancer therapy. Recently, Durdagi and colleagues used 32 male Wistar Albino rats and employed both ECG and cardiac biopsy for detecting any lesions in this tissue [49]. They indicated that MLT + Dox treatment increases the duration of some ECG features including QRS complex (P < 0.01), PR interval, T interval (P < 0.01), and QTc interval while Dox alone decreases these markers [49].
Conclusions
Since the discovery of MLT in 1958, the potential clinical applications of this agent have been increased steadily. In addition to the anti-cancer effects of MLT, it also has the capacity of increasing the efficacy of other therapeutic procedures such as chemotherapy. Due to the intense side-effects of chemotherapy and its negative impact on outcome and life quality, using MLT, which is essentially devoid of toxicity, in combination with chemotherapy should be considered as a option. Dox is an
Ethics approval and consent to participate
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Funding
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Author contributions
Parisa Maleki Dana, Fatemeh Sadoughi, Russel J.Reiter, Sotoudeh Mohammadi, Zahra Heidar, Masoumeh Mirzamoradi and Zatollah Asemi and contributed in the conception, design, and drafting of the manuscript.
All authors approved the final version of the manuscript.
Consent for publication
Not applicable.
Availability of data and material
Not applicable.
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgements
This study supported by Kashan University of Medical Sciences, Kashan, Iran.
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