No abstract

Tumour relapse, chemotherapy resistance, and metastasis continue to be unsolved issues in cancer therapy. A recent approach has been to scrutinise drugs used in the clinic for other illnesses and modify their structure to increase selectivity to cancer cells. Chloroquine (CQ) and hydroxychloroquine (HCQ), known antimalarials, have successfully treated autoimmune and neoplastic diseases. CQ and HCQ, well-known lysosomotropic agents, induce apoptosis, downregulate autophagy, and modify the tumour microenvironment. Moreover, they affect the Toll 9 / NF-κB receptor pathway, activate stress response pathways, enhance p53 activity and CXCR4-CXCL12 expression in cancer cells, which would help explain their effects in cancer treatment. These compounds can normalise the tumour-associated vasculature, promote the activation of the immune system, change the phenotype of tumour-associated macrophages (from M2 to M1), and stimulate cancer-associated fibroblasts. We aim to review the historical aspects of CQ and its derivatives and the most relevant mechanisms that support the therapeutic use of CQ and HCQ for the treatment of cancer.

BackgroundThe neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and mean platelet volume-to-platelet ratio (MPR) are combined hematology tests that predict COVID-19 severity, although with different cut-off values. Because sex significantly impacts immune responses and the course of COVID-19, the ratios could be biased by sex.PurposeThis study aims to evaluate sex-dependent differences in the contribution of NLR, PLR, MLR, and MPR to COVID-19 severity and mortality upon hospital admission using a sample of pneumonia patients with SARS-CoV-2 infection.MethodsThis single-center observational cross-sectional study included 3,280 confirmed COVID-19 cases (CDC 2019-Novel Coronavirus real-time RT-PCR Diagnostic) from Quito (Ecuador). The receiver operating characteristic (ROC) curve analysis was conducted to identify optimal cut-offs of the above parameters when discriminating severe COVID-19 pneumonia and mortality risks after segregation by sex. Severe COVID-19 pneumonia was defined as having PaO2 < 60 mmHg and SpO2 < 94%, whereas non-severe COVID-19 pneumonia was defined as having PaO2 ≥ 60 mmHg and SpO2 ≥ 94%.ResultsThe mortality rate of COVID-19 among men was double that in women. Severe COVID-19 pneumonia and non-surviving patients had a higher level of NLR, MLR, PLR, and MPR. The medians of NLR, MLR, and MPR in men were significantly higher, but PLR was not different between men and women. In men, these ratios had lower cut-offs than in women (NLR: 2.42 vs. 3.31, MLR: 0.24 vs. 0.35, and PLR: 83.9 vs. 151.9). The sensitivity of NLR, MLR, and PLR to predict pneumonia severity was better in men (69–77%), whereas their specificity was enhanced in women compared to men (70–76% vs. 23–48%).ConclusionThese ratios may represent widely available biomarkers in COVID-19 since they were significant predictors for disease severity and mortality although with different performances in men and women.

Twelve 7‐chloroquinoline derivatives were designed and synthesized using the principle of molecular hybridization through the coupling of 2‐[2‐(7‐chloroquinolin‐4‐ylthio)‐4‐methylthiazol‐5‐yl]acetic acid 1 with various benzoyl hydrazines 2a–l. The synthetic compounds were tested as antimalarials. Some of them showed an efficient in vitro activity as inhibitors of β‐hematin formation and an in vivo activity in a murine model, resulting in compounds 8 and 9 as the most active ones with IC50 values of 0.65 ± 0.09 and 0.64 ± 0.16 µM, respectively. The effects of the compounds on the cell viability, cell cycle, and apoptosis induction of A549 and MCF‐7 cancer cell lines were also examined. Our data showed that compounds 6 and 12 were the most active agents, decreasing the cell viability of MCF‐7 cells with IC50 values of 15.41 and 12.99 µM, respectively. None of the compounds analyzed significantly affected the viability of peripheral blood mononuclear cells. Also, significant induction of apoptosis was observed when both cancer cell lines were incubated with compounds 6 and 12. In MCF‐7 cells, treatment with these compounds led to cell cycle arrest in the G0/G1 phase. The results obtained suggest that these structures may be useful in developing new therapies for malaria and cancer treatment.