👤 Qin WW

In recent years, photodynamic therapy (PDT) and gas therapy (GT) have emerged as research hotspots due to their excellent cancer treatment efficacy. By combining the advantages of both, the simultaneous and controllable release of reactive oxygen species (ROS) and nitric oxide (NO) has become a possibility. This paper describes the design of two Ru(II) complexes, [Ru(bpy)₂(NFIP)](PF₆)₂ (Ru1, bpy = 2,2'-bipyridine, NFIP = 4-nitro-3-trifluoromethylaniline-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ru(phen)₂(NFIP)](PF₆)₂ (Ru2, phen = 1,10-phenanthroline), through the integration of the polypyridyl ruthenium structure and a photoresponsive NO donor. The structures and purity of the complexes were confirmed by several methods, including ¹H NMR, mass spectrometry, elemental analysis, high performance liquid chromatography (HPLC) and UV-Vis absorption spectra. Both complexes were demonstrated to efficiently generate singlet oxygen (¹O₂) (Φ_Δ = 0.40 and 0.44 in phosphate buffered saline (PBS) for Ru1 and Ru2, respectively) and release NO under visible light irradiation. Upon light exposure, Ru2 exhibited significant phototoxicity against human cervical cancer HeLa cells. In vitro experiments indicated that Ru2 elevated the levels of ROS and NO in HeLa cells when exposed to light, resulting in mitochondrial impairment and caspase-mediated cell death. Overall, Ru2 proves to be a potent phototherapeutic compound, capable of producing ROS and NO, thus providing precision in cancer phototherapy. Show less

Colorectal cancer is among the most common cancers worldwide and a frequent cause of cancer related deaths. Oxaliplatin is the first line chemotherapeutics for treatment, but the development of resistance leads to recurrence of oxaliplatin insensitive tumors. To understand possible mechanisms of drug tolerance we developed oxaliplatin resistant derivatives (OR-LoVo) of the established LoVo cell line originally isolated from a metastatic colon adenocarcinoma. We compared the microRNA (miRNA) expression profile of the cell pair and found expression of miR-29a-3p significantly increased in OR-LoVo cells compared to parent cells. In addition, miR-29a-3p was significantly elevated in tumor tissue when compared to matched surrounding tissue in human, suggesting potential clinical importance. Ectopic miR-29-a-3p expression induced chemoresistance in a number of different cancer cell lines as well as colorectal tumors in mice. We further demonstrated that miR-29-a-3p downregulates expression of the ubiquitin ligase component FEM1B and that reduction of Fem1b levels is sufficient to confer oxaliplatin resistance. FEM1B targets the glioma associated oncogene Gli1 for degradation, suggesting that increased Gli1 levels could contribute to oxaliplatin tolerance. Accordingly, knockdown of GLI1 reverted chemoresistance of OR-LoVo cells. Mechanistically, resistant cells experienced significantly lower DNA damage upon oxaliplatin treatment, which can be partially explained by reduced oxaliplatin uptake and enhanced repair. These results suggest that miR-29-a-3p overexpression induces oxaliplatin resistance through misregulation of Fem1B and Gli1 levels. TCGA analyses provides strong evidence that the reported findings regarding induced drug tolerance by the miR-29a/Fem1B axis is clinically relevant. The reported findings can help to predict oxaliplatin sensitivity and resistance of colorectal tumors. Show less

The combination of chemotherapeutic and photodynamic activities in an iridium-based molecular compound is less reported. Herein, two iridium complexes (IrC1 and IrC2) with β-carboline alkaloid ligands were designed and synthesized. Both complexes exhibited high anticancer activities with IC50 values of around 1 μM in the dark against several cell lines tested. Notably, the cytotoxicity of these two complexes against lung cancer (A549) cells increased significantly under light (425 nm) irradiation, with phototoxicity index (PI) values of 120 and 93, respectively. They were specifically enriched in the mitochondria. Cell-based assays demonstrated that IrC1 induced an increase in intracellular reactive oxygen species (ROS) levels, reduction in ATP production, mitochondrial DNA damage, an increase in lipid peroxidation levels, and proteasomal activity inhibition. Under light conditions (in some cases a two-photon laser was also applied), these effects were greatly enhanced. Overall, we have demonstrated that these iridium complexes have dual activities of chemotherapy and photodynamic therapy, which may help to design new metal-based anticancer agents for combined chemo-photodynamic therapy. Show less

Lysosomes play a critical role in the autophagy process. The impairment of lysosomes can affect the degradation of autophagic cargo, leading to the blockage of autophagy at the lysosomal stage and subsequent cell death. Herein, two phosphorescent Re(i) tricarbonyl complexes (Re1 and Re2) bearing β-carboline derivatives have been synthesized and characterized. Both complexes show pH-dependent phosphorescence, which can be used to specifically image the lysosomes. Cytotoxicity assay shows that they exhibit high anticancer activity and are able to overcome cross-resistance to cisplatin. Re2 can induce autophagy, which is blocked at the lysosomal stage due to lysosomal dysfunction, such as the decrease of cathepsin B activity, subsequently leading to both autophagy and apoptosis dependent cell death. In vivo studies revealed that it could significantly inhibit tumor growth. Show less