2.3.6. Others (Cancer, Inflammation, Cardiovascular Diseases)
Given the well-recognized properties of HCQ against inflammation, it is easily intuitable that this agent could possess interesting insights into cancer treatment. Chronic intestinal inflammation predisposes to the risk of colitis-associated colorectal cancer. In vivo, HCQ was demonstrated to interfere with cancer growth at different stages of development, both preventing tumorigenesis in the early phases and inhibiting tumor growth in the late phases in mice treated with azoxymethane and dextran sodium sulfate to induce cancer. In terms of animal survival, 120 days treatment with 50 mg/kg of HCQ intraperitoneal injection (i.p.) almost restored the survival rate to pre-treatment values and reduced the size of the tumor. The therapeutic effects of HCQ may be attributed to the significant inhibition of pro-tumorigenic and pro-inflammatory cytokines, which not only limited the tumor progression by reducing inflammation of lamina propria, but also decreased the ROS production in macrophages [111]. Many others are the mechanisms by which HCQ exerts anticancer effects, mainly in synergism with conventional chemotherapic drugs, as discussed later.
Regarding the cardioprotective effect, this review has already focused on the positive impact of HCQ on cardiovascular issues in autoimmune patients. A protective effect of HCQ on neonatal rat cardiomyocytes was proven by Bourke, McCormick, Taylor, Pericleous, Blanchet, Costedoat-Chalumeau, Stuckey, Lythgoe, Stephanou and Ioannou [112] in ischemia-reperfusion animal models. The pharmacological preconditioning with HCQ seems to be a good strategy to protect from ischemia-reperfusion injury. The pretreatment with daily gavage of 200 mg/kg of HCQ, indeed, reduced the cardiac infarct size by 47%. The mechanism underlying this effect is linked to the inhibition of apoptosis and total cell death in neonatal rat cardiomyocytes. The atherosclerotic process contributes to increasing the risk of heart failure. The etiology of this condition is still not clear. A hypothesis supposes that the accumulation of lipids in vessels caused the formation of atherosclerotic plaques that are responsible for vessel narrowing, shear stress, and platelet aggregation. HCQ decreased free-fatty acids, triglycerides, total cholesterol, and LDL levels in diabetic rats under doses of 200 mg/kg/day [106]. Moreover, HCQ (10 mg/kg/day) was demonstrated to exhibit functional and structural protection in 40 high-fat diet mice, by reducing atherosclerotic area by 60% with respect to the control [114]. These favorable effects at the metabolic level might be due to its anti-inflammatory power that influences many other biological activities. In gastrointestinal inflammations, mainly in inflammatory bowel disease, HCQ suppressed pro-inflammatory cytokines and enhanced the expression of ILs involved in anti-inflammatory processes. In mouse models of colitis, the HCQ methacryloylated form (30 mg/kg) avoided systemic absorption, accumulating in the gastrointestinal tract, where alterations in the immune homeostasis of the intestinal mucosa had a positive impact on the disease [74]. Inflammation, together with alterations in the immune system, are at the basis of pulmonary hypertension. The ability of HCQ to interfere with the production of pro-inflammatory cytokines from monocytes and lymphocytes might underlie the observed improvements in systolic pressure and ventricular hypertrophy, in rats with pulmonary hypertension treated with 50 mg/kg/day i.p. of HCQ for 20 days [115]. Likewise, in endometriosis, the abnormal presence of endometrium in other organs leads to a chronic inflammatory status that could be affected by HCQ intervention. Ruiz, Rockfield, Taran, Haller, Engelman, Flores, Panina-Bordignon and Nanjundan [116] observed an increment of peritoneal macrophages in mouse models of endometriosis under HCQ (60 mg/kg i.p.). In their role of scavengers, abnormalities in these cell populations may lead to an accumulation of endometrial cells, with impairment of the disease. Moreover, histopathologic improvement of lesions was observed, probably due to the inhibition of autophagy by HCQ that alters anoikis response of endometrial cells [116].