Simultaneous induction of apoptosis and ferroptosis by a novel thiolato-bridged manganese(I)-based CO-releasing molecule in pancreatic and prostate cancer cells.
Jul 2026· Archives of Biochemistry and Biophysics· Vol 784, pp.
110942
· 0 citations· 78 references
Medicine
TL;DR
It is established that S-MnC is a potent, dual-action therapeutic agent that mediates both apoptosis and ferroptosis, offering a promising strategy to overcome drug resistance in aggressive, metastatic cancers and to enhance therapeutic efficacy.
Abstract
Due to the invasive nature of cancer cells, therapies targeting a single cell death pathway alone often encounter drug resistance; therefore, the development of novel therapeutic strategies, such as the dual induction of apoptosis and ferroptosis, is warranted. This study investigated the anticancer mechanism of the newly synthesised thiolato-bridged manganese-based CO-releasing molecule (S-MnC) in highly metastatic pancreatic (PANC-1) and prostate (PC-3) cancer cells. The myoglobin assay showed controlled liberation of approximately 1.5 CO equivalents per S-MnC molecule in the dark, and approximately 1.1 equivalents under UV irradiation, consistent with a sustained single-donor profile. S-MnC induced apoptosis through ROS generation via Fenton-like reaction, mitochondrial membrane disruption, caspase activation, and DNA damage, culminating in G1-phase cell cycle arrest. Ferroptosis was triggered concurrently via p53-mediated suppression of SLC7A11 and GPX4, leading to GSH depletion, and iron overload was evident, with upregulated TFR1 expression. Notably, a crosstalk between these two cell death pathways was demonstrated, as ferrostatin pretreatment rescued the expression of apoptotic genes, suggesting that ferroptotic signalling actively contributes to the apoptotic response induced by S-MnC. Moreover, S-MnC also exhibited antimetastatic potential by suppressing MMP-2 and MMP-9. S-MnC showed promising binding potential towards pancreatic and prostate cancer-specific targets, mesothelin and prostate cancer-specific membrane antigen, with predicted binding energies of -8.4 and -9.1 kcal/mol, respectively. Our results, for the first time, establish that S-MnC is a potent, dual-action therapeutic agent that mediates both apoptosis and ferroptosis, offering a promising strategy to overcome drug resistance in aggressive, metastatic cancers and to enhance therapeutic efficacy.
Ferroptosis has emerged as a potential therapeutic target for chemotherapy of cancer. However, non-small cell lung cancer (NSCLC) exhibits high tolerance to ferroptosis due to inherent resistance. To increase NSCLC vulnerability, we present a TRPV1-targeting approach that self-delivers intracellular irons and TRPV1 agonist (N-oleoyldopamine, OLDA) to provoke simultaneous apoptosis and ferroptosis in NSCLC. Intracellular release of OLDA activates TRPV1 channels, triggering Ca2+ overload and mitochondrial/ER stress to induce apoptosis, while Fe3+ ions drive Fenton reactions, depleting GPX4/GSH and elevating lipid peroxides to induce ferroptosis. FeOLDA demonstrated selective cytotoxicity toward A549 NSCLC cells over normal bronchial epithelial BEAS-2B cells. In vivo studies demonstrate that FeOLDA effectively suppresses tumor growth without weight loss or multi-organ toxicity associated with cisplatin. This dual-action platform offers a lung cancer-targeted and efficient strategy for NSCLC treatment.
Ziyi Wang, Liang Shao, Chunbao Wang et al.· Biomaterials Science· 0 citations
Type-I photodynamic therapy (PDT) is a promising strategy for treating hypoxic tumors because it overcomes the oxygen dependence of traditional PDT. However, the rational design of a potent Type-I photosensitizer that simultaneously achieves subcellular organelle targeting and activates the pyroptotic cell-death pathway remains a formidable challenge. Herein, we report the development of a "Swiss-army-knife" iridium(III) complex, termed Mito-Ir, that concurrently integrates mitochondria targeting, phosphorescence imaging, Type-I/II reactive oxygen species generation, photocatalytic oxidation of 1,4-dihydronicotinamide adenine dinucleotide (NADH) and pyroptosis induction, offering a "one-for-all" platform for high-performance breast-cancer PDT. Upon light irradiation, Mito-Ir triggers severe mitochondrial dysfunction, activating the caspase-3/GSDME pathway to induce pronounced pyroptosis. This pathway not only overcomes apoptosis resistance but also elicits immunogenic cell death through the release of cytokines and damage-associated molecular patterns, thereby activating antitumor immunity. Both in vitro and in vivo studies confirmed its potent antitumor efficacy, underscoring its potential as a pioneering pyroptosis-based therapeutic strategy for breast cancer.
C. Wei, Kuang Xu, Jie Peng et al.· Journal of Medicinal Chemist...· 0 citations
Plasma-based approaches are attracting interest as potential anticancer strategies due to their ability to generate reactive species that damage tumor cells. However, clinical translation remains limited by challenges in biocompatibility, reproducibility, and chemical tunability. In this study, we utilized a nitrogen-oxygen gas mixture to generate a controllable spectrum of reactive species and evaluated its effects in endometrial (HEC1A), cervical (HeLa), melanoma (B16F10), and lung (H1299) cancer models. Nitrogen-oxygen plasma treatment preferentially reduced cancer cell viability compared to normal fibroblasts in vitro. Mechanistically, plasma exposure increased intracellular oxidative stress, and co-treatment with GSH attenuated cytotoxicity, indicating a central role for reactive species. Apoptosis was supported by Annexin V/PI staining, caspase-3 and PARP cleavage, mitochondrial depolarization, and increased γH2AX, phospho-p53, BiP, and CHOP. Transcriptomic profiling revealed activation of apoptotic pathways alongside modulation of ferroptosis-associated genes. Ferrostatin-1 partially rescued cell viability, linking cytotoxicity to lipid peroxidation, whereas iron chelation did not reduce lipid peroxidation. These findings indicate a contribution of lipid peroxidation without canonical iron-dependent ferroptosis. In vivo, treatment significantly suppressed tumor growth in a B16F10 melanoma allograft model following intratumoral administration. Together, these results demonstrate that nitrogen-oxygen plasma induces apoptosis with additional oxidative lipid damage, supporting its therapeutic potential.
Bum-Ho Bin, Sofia Brito, Sun Ju Park et al.· Scientific Reports· 0 citations
Ferroptosis is a unique type of programmed cell death caused by excessive lipid peroxidation and represents a vulnerability in certain types of cancer. However, the signaling mechanisms that modulate ferroptosis and its functional consequence on the tumor microenvironment are poorly understood. Here, we demonstrate an inhibitory effect of mitochondrial calcium uniporter (MCU) on ferroptosis during embryogenesis and tumor development. MCU-dependent production of metabolite acetyl-coenzyme A (acetyl-CoA) supports the normal function of glutathione peroxidase 4 (GPX4), a critical gatekeeper of ferroptosis. Mechanistically, acetylation of GPX4 on lysine 90 (K90) prevents the formation of a detrimental salt bridge between K90 and aspartate 23, therefore protecting GPX4 enzymatic activity and avoiding ferroptosis. Deletion of MCU in cancer cells caused a robust antitumor T cell response and significantly blunted tumor growth. Thus, our findings indicate MCU-mediated acetyl-CoA metabolism as a critical anti-ferroptosis mechanism, which can be investigated as potential therapeutic candidate for tumor treatment.
Jianwen Chen, Bao Zhao, H. Dong et al.· Proceedings of the National...· 0 citations
Breast cancer is the most frequently diagnosed cancer in the world, but its treatment effect is limited, so new treatment strategies are needed. An iron chelator, 2,2'-di-pyridineketone hydrazone dithiocarbamate butyric acid ester (DpdtbA), exerts significant growth inhibition in breast cancer cell lines. Our data showed that DpdtbA treatment significantly promoted extensive cytoplasmic vacuolization derived from the endoplasmic reticulum, mitochondrial swelling, and Alix downregulation in MDA-MB-231 and SK-BR-3 cell lines. Furthermore, cytoplasmic vacuolation could be abolished by cycloheximide (CHX) and antioxidant N-acetylcysteine (NAC), indicating that vacuole formation required new protein synthesis and was ROS-dependent. These results support that DpdtbA is able to induce paraptosis, a programmed cell death pattern. The enhanced cytoplasmic Ca2+after DpdtbA treatment or deceased Ca2+ upon co-treatment with the Ca2+ chelator (BAPTA-AM) prompted that ROS production may partially correlate with the Ca2+-mediated decrease in mitochondrial membrane potential. In addition, DpdtbA triggered ER stress and accumulation of unfolded proteins, leading to the activation of p-PERK/p-EIF2α and p-IRE1/ATF4/chop pathway, inactivation of ATF6 (activating transcription factor 6) that may contribute to the anti-proliferative effect. Furthermore, our data showed that DpdtbA treatment not only led to excessive activation of MAPKs (mitogen activated protein kinases) signaling, but also resulted in inactivation of the PI3K/AKT/mTOR pathway, both of which were involved in the regulation of paraptosis. The results demonstrated that paraptotic cell death induced by an iron chelator in breast cancer cells was partially involved in Ca2+-mediated ROS production, UPR(unfolded protein response)/MAPKs activation, and PI3K/AKT/mTOR inactivation.
Lei Yuan, Siwen Dong, Yong Shao et al.· Scientific Reports· 0 citations
SIRT3, a key mitochondrial deacetylase that regulates metabolic adaptation, oxidative stress, and apoptosis in cancer cells, has emerged as a promising therapeutic target in cancer treatment. 4,4'-dimethoxychalcone (DMC) is a natural chalcone derivative extracted from Angelica keiskei. In this study, we demonstrated that DMC induces thermosensitive impairment in SIRT3-associated mitochondrial signaling. A non-lethal temperature (42 °C) facilitates the interaction between DMC and the catalytic pocket of SIRT3, leading to preferential suppression of SIRT3 activity and consequently sensitizing HeLa cells to robust apoptotic signaling. This inhibition was accompanied by increased SOD2 acetylation and reduced SOD2 abundance, driving accumulation of oxidative stress, which triggers loss of mitochondrial membrane potential (ΔΨm), and pronounced caspase activation. Concomitantly, γ-H2AX nuclear foci formation and dual-phase cell-cycle arrest at the G1/S and G2/M checkpoints were associated with activation of p53/p21 and ATM/Chk2 signaling. In addition, cell migratory capacity was significantly impaired, as evidenced by reduced expression of MMP2 and MMP9. Notably, this inhibition impairs autophagic and mitophagic flux as well as lysosomal function, thereby preventing cytoprotective responses and facilitating cell death. Importantly, enforced SIRT3 overexpression reverses these effects, restores mitochondrial function, reactivates autophagic activity, and attenuates apoptotic cell death. Collectively, our findings identify DMC as a thermosensitive inhibitor of SIRT3 and provide mechanistic insights into its potential to disrupt mitochondrial homeostasis for targeted cancer therapy.
