دانلود رایگان مقاله اثر درمانی هیدروکسی کلروکین در سرطان روده بزرگ

abstract

Chronic inflammation in the intestine is a strong risk factor for colitis-associated colorectal cancer (CAC). Hydroxychloroquine (HCQ) is widely used as an anti-inflammatory drug in the treatment of immunemediated inflammatory disorders and various tumors. However, little is known regarding the effects of HCQ on colitis-associated tumorigenesis. In this study, mice treated with HCQ showed a significant reduction in early-stage colitis following azoxymethane (AOM)/dextran sodium sulfate (DSS) administration, as well as a remarkable inhibition of colonic tumorigenesis and tumor growth at late stages of CAC. Mechanistically, the therapeutic effects of HCQ were attributed to inhibition of inflammatory responses and production of mutagenic reactive oxygen species (ROS) in immune cells and subsequent promotion of apoptosis and cell cycle arrest in tumor cells. Furthermore, we found that HCQ inhibited the production of inflammatory cytokines and ROS in response to toll-like receptor 4 (TLR4) activation in macrophages. Our data presented herein may help guide the clinical use of HCQ as a prevention and treatment strategy for CAC.

4. Discussion

TNFa antagonists are ubiquitously used as induction and postremission therapies for patients with IBD and an effective preventative therapy for colitis-associated tumorigenesis, which elicit an anti-inflammation effect on IBD and CAC [34,35]. CQ and its analog, HCQ, the two most frequently used 4-aminoquinolone antimalarial drugs, due to their ability to directly inhibit inflammatory cytokines [13], have been used to treat autoimmune diseases for decades, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). With regard to the therapeutic effects of CQ/ HCQ in IBD, one previous study has demonstrated that shortduration CQ treatment is safe for mild to moderately active UC [25]. Similarly, in our study, HCQ significantly reduced the mortality of mice with DSS-induced acute colitis (Fig. 1A). Furthermore, HCQ ameliorated colitis in the early stage of AOM/DSS-induced murine CAC (Fig. 1B–H) and subsequently suppressed tumorigenesis and tumor growth (Fig. 2). Interestingly, the effects of HCQ on tumorigenesis were more striking compared to the effect on acute colitis following the first cycle of DSS administration. There are two reasonable possibilities for this difference. One is that acute colitis was induced only by one cycle of DSS administration, while CAC formed after four cycles of DSS administration, HCQ ameliorated CAC dramatically in that the anti-inflammatory effect of HCQ accumulated over time. In addition, HCQ suppressed tumor proliferation and promoted tumor apoptosis, which also attributed to the inhibition of CAC at the late stage.