Evoking Ferroptosis by Synergistic Enhancement of a Cyclopentadienyl Iridium-Betulin Immune Agonist.

Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation (LPO) with the potential for antitumor immunity activation. In this study, a nonferrous cyclopentadienyl metal-based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl (Ir-Bet) was developed by a metal-ligand synergistic enhancement (MLSE) strategy involving the reaction of [Ir(Cp*)Cl]2 Cl2 with the natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir-Cp*) species as Ir-Bet not only tremendously enhanced the antiproliferative activity toward cancer cells, but also activated ferritinophagy for iron homeostasis regulation by PI3K/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evoked an immune response by nuclear factor kappa-B (NF-κB) activation of Ir-Cp* species. Further immunogenic cell death (ICD) occurred by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. An in vivo vaccination experiment demonstrated desirable antitumor and immunogenic effects of Ir-Bet by increasing the ratio of cytotoxic T cells (CTLs)/regulatory T cells (Tregs).

Selectively attacking tumor cells of Ru/Ir-arene complexes based on meclofenamic acid via cyclooxygenase-2 inhibition.

Breast cancer (BC) is one of the most common malignant tumors and often accompanied by inflammatory processes. Inflammation is an essential component of the tumor microenvironment, which might influence tumor proliferation and metastasis. Herein, three metal-arene complexes MA-bip-Ru, MA-bpy-Ir, and MA-bpy-Ru were prepared by tethering the non-steroidal anti-inflammatory drug meclofenamic acid (MA). Among them, MA-bip-Ru and MA-bpy-Ir showed lower cytotoxicity towards cancer cells, but MA-bpy-Ru showed significantly high selectivity and cytotoxicity towards MCF-7 cells through the autophagic pathway and exhibited no toxicity against normal HLF cells, showing potential for selective treatment of tumor cells. MA-bpy-Ru could also effectively destroy the 3D multicellular tumor spheroids, demonstrating its potential for clinical application. Besides, MA-bip-Ru, MA-bpy-Ir, and MA-bpy-Ru exhibited anti-inflammatory properties superior to MA, notably downregulating the expression of cyclooxygenase-2 (COX-2) and inhibiting the secretion of prostaglandin E2 in vitro. These findings demonstrated that MA-bpy-Ru was capable of intervening in inflammatory processes and showed the potential of MA-bpy-Ru to act as a selective anticancer agent, thus presenting a new mechanism of action for metal-arene complexes.

Immunostimulation with chemotherapy of a ruthenium-arene complex via blockading CD47 signal in chronic myelogenous leukemia cells.

Combination of novel immunomodulation and traditional chemotherapy has become a new tendency in cancer treatment. Increasing evidence suggests that blocking the "don't eat me" signal transmitted by the CD47 can promote the phagocytic ability of macrophages to cancer cells, which might be promising for improved cancer chemoimmunotherapy. In this work, we conjugated CPI-alkyne modified by Devimistat (CPI-613) with ruthenium-arene azide precursor Ru-N3 by copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to construct Ru complex CPI-Ru. CPI-Ru exhibited satisfactory cytotoxicity towards the K562 cells while nearly non-toxic towards the normal HLF cells. CPI-Ru has been demonstrated to cause severe damage to mitochondria and DNA, ultimately inducing cancer cell death through the autophagic pathway. Moreover, CPI-Ru could significantly downregulate the expression of CD47 on the surface of K562 accompanied by the enhanced immune response by targeting the blockade of CD47. This work provides a new strategy for utilizing metal-based anticancer agents to block CD47 signal to achieve chemoimmunotherapy in chronic myeloid leukemia treatment.

The non-linear association between ascending aorta diameter and risk of 12-month mortality in Chinese patients with heart failure: A retrospective cohort study.

Background: There is no conclusive proven link between ascending aorta diameter (AoD) and the risk of death from heart failure (HF). As a result, a retrospective cohort analysis was carried out to determine whether AoD is associated with 12-month mortality in Chinese HF patients. Methods: From January 2017 to March 2020, we collected data on 575 Chinese patients with HF. The exposure and outcome variables were baseline AoD and 12-month risk of mortality (all-cause + cardiac origin), respectively. Data on demographics, drug usage, clinical characteristics, recognized indicators of HF, and comorbidities were included as covariates. To investigate the independent relationships of AoD with the risk of 12-month death, binary logistic regression and two-piecewise linear models were utilized. Results: Our findings imply that there was a non-linear relationship between AoD and the risk of 12-month mortality. For the AoD range of 23 to 37, there was no association with the risk of cardiac mortality [odds ratio (OR) 0.78, 95% confidence interval (CI), 0.62-1.04]. In the AoD range of 37-49, however, the risk of 12-month cardiac death increased by approximately 70% for every 1 mm increase in AoD (OR 1.70, 95% CI, 1.13-2.55). When all-cause death was chosen as the outcome, the same outcome was shown. Conclusion: An AoD larger than 37 mm is a hazardous threshold for Chinese HF patients. Beyond this limit increased the risk of cardiac death by 70% for every 1 mm increase in AoD.

Non-linear association of cystatin C and all-cause mortality of heart failure: A secondary analysis based on a published database.

Background: Prior reports have revealed that basal Cystatin-C (CysC) is positively associated with all-cause death in patients with heart failure (HF). Yet, this positive association is not necessarily generalizable to Chinese HF patients due to methodological limitations and lack of data from Chinese patients. Materials and methods: We performed secondary data mining based on a retrospective cohort dataset published on the internet. This dataset contains 2008 patients with HF who were admitted to a tertiary hospital in Sichuan Province, China from 2016 to 2019. The exposure variable was baseline CysC and the outcome variable was all-cause death on day 28, day 90, and month 6. Covariates were baseline measurements, including demographic data, drug use, comorbidity score, organ function status (heart, kidney), and severity of heart failure. Results: Among 1966 selected participants, the mortality rates at 28 days, 90 days and 6 months were 1.83% (36/1966), 2.09% (41/1966) and 2.85% (56/1966) respectively. After adjustment for confounders, the non-linear associations between CysC and all-cause deaths were observed. We calculated the inflection points were about 2.5 mg/L of CysC. On the right of inflection point, each increase of 1 mg/L in CysC was associated with an increase in the risk of 28-day mortality (Relative risk [RR], 2.07; 95% confidence interval [CI], 1.09 to 3.93; P = 0.0266), 90-day mortality (RR, 2.51; 95% CI, 1.38 to 4.57; P = 0.003), and 6-month mortality (RR,2.25; 95% CI, 1.37 to 3.70; P < 0.001). Conclusion: Our findings suggest that values about 2.5 mg/l of cystatin could be a danger threshold for the short-term risk of death in heart failure. Exceeding this threshold, for every 1 mg/L increase in CysC, the risk of all-cause mortality increased by more than one time.

The cyclometalated iridium (III) complex based on 9-Anthracenecarboxylic acid as a lysosomal-targeted anticancer agent.

9-Anthracenecarboxylic acid (9-Ac) was reported early as a chloride channel inhibitor and was found to exhibit significant anti-proliferative activity on leukemic cells, but has not been researched in solid tumor cells. Herein, a 9-anthraceneic acid derivative was introduced into the cyclometalated Iridium (III) species to construct a novel Iridium (Ir) complex Ir-9-Ac, [Ir(ppy)2(9-Ac-L)]PF6 (ppy = 2-phenylpyridine, 9-Ac-L = N-((4'-methyl-[2,2'-bipyridin]-4-yl)methyl)anthracene-9-carboxamide), which could accumulated in lysosomes. Ir-9-Ac showed good cytotoxic activity against several tumor cell lines, notably on A549 cells. Besides Ir-9-Ac could inhibit the cell colony formation and growth of the 3D cell spheroids, demonstrating the potential to suppress tumors in vivo. This design provided a platform for the design of cyclometalated Iridium (III) anticancer complexes.