The effect of 3 and 6 weeks of aerobic exercise on the growth and inflammatory factors of the liver following the induction of different doses of doxorubicin

Doxorubicin (DOX) is an antibiotic with a wide range of anti-tumor and anti-cancer (anti-neoplastic) functions and has been widely used in the treatment of various cancers since the late 60s. Unfortunately, the clinical use of this highly effective anticancer drug has been limited, and this is due to the severe toxic effects of this drug on some body tissues, including the heart, liver, kidney, and nervous system. The effect of 3 and 6 weeks of aerobic exercise on the growth and inflammatory factors of the liver following the induction of different doses of doxorubicin in male rats. 72 Wistar male rats were randomly divided into two control and training groups. The training group itself was divided into 3 and 6 weeks. The training program included running on the treadmill for 25-54 minutes per day at a speed of 15-20 meters per minute, 5 sessions per week for 3 and 6 weeks. At the end of the training period, the mice of the control and training groups were again randomly divided into subgroups of doxorubicin (10 mg/kg and 20 mg/kg) and saline (0.9%). Both injections were performed 24 hours after the last training session and the rats were killed 24 hours later. The levels of growth and inflammatory factors were measured through the ELISA method. The data were analyzed by one-way analysis of variance and Tukey's post hoc test (LSD) at the P?0.05 level. Induction of doxorubicin (10 and 20 mg/kg) led to the imbalance of growth and inflammatory indicators in the liver. 3 led to a significant increase in IGF-1 and 6 weeks of training led to a significant decrease in IGF-1, a significant increase in IGFBP-3 and IGFBP-3/IGF-1 compared to the control + saline group. Despite this, after 3 weeks of aerobic exercise and DOX injection (10 and 20 mg/kg), all indicators showed a non-significant increase and decrease in the dose of 10 and a significant decrease in IGF-1, IGF-1/IGFBP-3 and IFN-? compared to the control group + doxorubicin 10 or 20 mg/kg. Also, after 6 weeks of aerobic exercise and DOX injection (10 and 20 mg/kg), a significant decrease in IGF-1 and IGF-1/IGFBP-3 and a significant increase in IGFBP-3 and a significant decrease in IGF-1 and IGF-1/IGFBP-3 and IFN-? were observed, respectively, compared to the control group + doxorubicin 10 or 20 mg/kg. On the other hand, there was no significant difference between treatment with doxorubicin 10 and 20 mg/kg. The results suggest that liver protection caused by chronic exercise training in mice treated with DOX is associated with the moderation of growth and inflammatory factors. Introduction

Cancer is a major public health problem in the United States and many other regions of the world. One in four deaths in the United States is caused by cancer. The American Cancer Society estimates the number of new cancer cases and deaths in the United States each year, and with the most recent cancer incidence data compiled, a total of 1,638,910 new cancer cases and 577,190 cancer deaths occurred in the United States in 2012. During the last 5 years, the rate of cancer prevalence in men has decreased (up to 0.6% per year) and was stable in women, while the cancer mortality rate has decreased by 1.8% per year in men and 1.6% per year in women. Doxorubicin is a chemotherapy drug used to treat many different types of cancer. Its other name is Adriamycin and it belongs to the family of anthracycline antibiotics and is made from Streptomyces bacteria [2]. Oxidative stress and free radical formation, which involves the reaction of doxorubicin with iron, are believed to play a critical role in the mechanism of doxorubicin toxicity.  Doxorubicin is significantly toxic to many tissues and organs, but its heart and liver toxicity is one of the limiting factors of this drug in cancer treatment [137]. Therefore, adopting any non-pharmacological strategy, including regular aerobic activity, can have a significant effect on preventing many problems in the body's systems. The current study seeks to find a strategy to reduce the side effects caused by the use of doxorubicin, and in this regard, to investigate the effect of 3 and 6 weeks.The present study seeks to find a strategy to reduce the side effects caused by the use of doxorubicin, and in this regard, investigates the effect of 3 and 6 weeks of aerobic exercise on growth and inflammatory factors following hepatotoxicity caused by the induction of different doses of this drug.

1-2. Statement of the problem

According to the report of the American Health Association, 7.6 million people died of cancer in 2007. Therefore, in recent years, extensive efforts have been made by researchers to treat or slow down the growth of cancer cells. Doxorubicin (DOX) [1] is an antibiotic with a wide range of anti-tumor and anti-cancer (anti-neoplastic) [3,28,46,132,167,172] and has been widely used in the treatment of various cancers since the late 60s [4]. Unfortunately, the clinical use of this highly effective anticancer drug has been limited, and this is due to the severe toxic effects of this drug on some body tissues, including the heart, liver, kidney, and nervous system. It is believed that several molecular mechanisms, including the production of reactive oxygen species [2] (ROS) [138,5,47,174] and the stimulation of cell death [3] (apoptosis) [57,92] play a pivotal role in this cytotoxic process. In this regard, significant efforts have been made by researchers in the fields of medicine [46,132,172] and sports [3,4,167,93] to develop strategies to prevent toxicity caused by DOX, especially in heart tissue. In a study, Babaei et al.[132] reported the protective effect of morphine in DOX-induced cardiotoxicity. Other researchers also showed the protective effect of tetradrine [4] and amifostine [5] against cardiac damage and cardiotoxicity caused by DOX [46, 172]. While few studies have been conducted on the toxic effect of DOX in the liver tissue.

         Researchers investigated several indicators related to the growth and spread of cancer cells. The IGF system plays a critical role in cell proliferation. It includes IGF-1 and IGF-2 and families of IGF-binding proteins (IGFBP) that specifically bind to IGF [178]. Studies indicate that IGFBP dysregulation occurs in complications such as neuroblastoma [6], nephroblastoma [7] and acute lymphoblastic leukemia [8] [178]. Therefore, there is growing evidence that the IGF system is used as a panel of tumor markers for histological diagnosis in various cancer-related diseases. In this regard, it was reported that insulin-like growth factor [9] (IGF-1) and IGF-binding protein-3 [10] IGFBP-3) and IGF-binding protein-1 [11] IGFBP-1) are associated with increased risk of breast cancer in premenopausal women [133]. Recently, the results of the analysis of 17 studies conducted in this field show that the levels of IGF-1 are positively related to the estrogen receptor regardless of the menopausal status [132]. However, it has not been determined whether the implementation of sports training can affect the levels of IGF-1 and proteins connected to it.  In addition, it is not known what effect induction of DOX with two doses of 10 and 20 mg per kilogram of body weight has on these growth factors in liver tissue and whether performing 3 and 6 weeks of aerobic exercises before the induction of these doses can affect the process of changes in these indicators? In spite of the mentioned cases, although in young women, it has been determined that strength training reduces IGF-1 [139]. But there are very few longitudinal studies on the effects of IGF-1 protein training. We hypothesize that doing exercise will reduce IGF-1, increase the levels of proteins connected to it and reduce the ratio of IGF-1 to IGFBP-3, and in this way will reduce the risks associated with cancer. Also, reports indicate that inflammation through mechanisms such as the production of cytokines and growth factors and the production of ROS and the accumulation of reactive nitrogen species[12] (RNS) may play a role in the generation of cancer cells. On the other hand, researchers reported that performing physical activity in a proper way inhibits inflammatory indicators caused by chronic diseases, such as interleukins and interferon gamma, and in this way maintains and restores the homeostasis of various body systems. However, the preventive effect of different training periods (3 and 6 weeks) on the changes, especially following the induction of DOX and oxidative stress and cardiotoxicity caused by it, has not been investigated so far.