Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages.

BACKGROUND: Lysosome-associated agents have been implicated as possible chemo-sensitizers and immune regulators for cancer chemotherapy. We investigated the potential roles and mechanisms of hydroxychloroquine (HCQ) in combination with chemotherapy in lung cancer treatment. METHODS: The effects of combined treatment on non-small cell lung cancer (NSCLC) were investigated using cell viability assays and animal models. The influence of HCQ on lysosomal pH was evaluated by lysosomal sensors and confocal microscopy. The effects of HCQ on the tumour immune microenvironment were analysed by flow cytometry. RESULTS: HCQ elevates the lysosomal pH of cancer cells to inactivate P-gp while increasing drug release from the lysosome into the nucleus. Furthermore, single HCQ therapy inhibits lung cancer by inducing macrophage-modulated anti-tumour CD8+ T cell immunity. Moreover, HCQ could promote the transition of M2 tumour-associated macrophages (TAMs) into M1-like macrophages, leading to CD8+ T cell infiltration into the tumour microenvironment. CONCLUSIONS: HCQ exerts anti-NSCLC cells effects by reversing the drug sequestration in lysosomes and enhancing the CD8+ T cell immune response. These findings suggest that HCQ could act as a promising chemo-sensitizer and immune regulator for lung cancer chemotherapy in the clinic.

Cyclooxygenase-2 polymorphisms and bladder cancer risk: a meta-analysis based on case-control studies.

The current meta-analysis incorporating 15 case-control studies involving 4,138 cases and 4,269 controls was performed on the basis of a systematical search in electronic databases for a more precise estimation on the associations of three common polymorphisms -765 G>C (rs20417), -1195G>A (rs689466) and +8473 C>T (rs5275) in Cyclooxygenase-2 (Cox-2) gene with the susceptibility to bladder cancer. The results showed that there was a significant association between rs5275 polymorphism and bladder cancer risk (C vs. T; OR=0.84; CC vs. TT: OR=0.76), especially among Chinese (CC vs. TC+TT: OR=0.48) and American (C vs. T; OR=0.83; TC vs. TT: OR=0.73; CC+TC vs. TT: OR=0.73). and the rs20417 polymorphism was significantly associated with an increased risk of bladder cancer among Chinese (C vs. G: OR=1.46; GC vs. GG: OR=1.49; CC+GC vs. GG: OR=1.51) and Indian (GC vs. GG: OR=1.63; CC+GC vs. GG: OR=1.46), but a reduced risk among American (C vs. G: OR=0.81; GC vs. GG: OR=0.76; CC+GC vs. GG: OR=0.76). Additionally, we found that the rs689466 polymorphism was associated with a decreased risk of bladder cancer in Indian (GA vs. GG: OR=0.68; AA vs. GG: OR=0.39).The present meta-analysis suggests that Cox-2 rs5275 polymorphism may contribute to the risk of bladder cancer, particularly among Chinese and American. The rs20417 polymorphism may play a protective role in the development of bladder cancer in Indian and Chinese but act as a risk factor among American, while the rs689466 polymorphism was more likely to be associated with a decreased risk of bladder cancer in Indian.