Chien-Chih Chiu

Acylthiourea ligands, featuring hard (N, O) and soft (S) donor atoms, enable diverse coordination modes in half‐sandwich Ru(II)‐ p ‐cymene complexes. Herein, we report the synthesis and full characterization of eight half‐sandwich Ru(II)‐ p ‐cymene complexes, comprising four monodentate ( 1m – 4m ) and four bidentate ( 1b – 4b ) species prepared under distinct synthetic conditions. The structures of the complexes 1m , 2m , 3m , 3b , and 4b were confirmed by single‐crystal X‐ray diffraction, while FT‐IR, UV–vis, ESI‐MS, and ¹ H/ ¹³ C NMR spectroscopy unambiguously distinguish the two binding modes. The reversible coordination mode was monitored by ¹ H NMR and UV–vis spectroscopy, with base‐induced deprotonation favoring bidentate binding and HCl addition regenerating the monodentate form. Cytotoxic assays revealed that metal coordination markedly enhanced the antiproliferative activity of the ligands. Most bidentate complexes exhibited higher cytotoxicity than their monodentate analogues. In particular, 2b displayed a sixfold increase in potency (IC ₅₀ = 6.05 μM) compared to 2m (36.4 μM) and showed much lower toxicity toward normal ARPE‐19 cells (IC ₅₀ = 55.0 μM), indicating greater selectivity toward cancer cells. Molecular docking suggests DNA groove binding as the anticancer mechanism, highlighting the role of bidentate coordination, with 2b identified as the most promising Ru(II)‐ p ‐cymene complex.

Breast cancer is the most common cancer in women and a leading cause of cancer-related mortality worldwide. Most anticancer drugs act against cancer cells by inducing apoptotic pathways; unfortunately, chemoresistance, especially apoptosis resistance, contributes to poor outcomes in patients with breast cancer. Paraptosis is a type of nonapoptotic programmed cell death characterized mainly by cytoplasmic vacuolization and endoplasmic reticulum (ER)/mitochondrial swelling, which may provide a promising strategy for overcoming chemotherapy resistance. We investigated the effects of diphenyl disulfide (DPDS) on two breast cancer cell subtypes, MDA-MB-231 (triple-negative) and MCF-7 (luminal A). Our findings demonstrate that DPDS exerts significant cytotoxic effects on these two breast cancer cell lines. In addition, DPDS induced the accumulation of vacuoles in cells and downregulated the paraptosis marker Alix while increasing the expression of the ER stress markers BIP/Grp78 and IRE-1 and oxidative stress owing to the accumulation of reactive oxygen species (ROS), eventually inducing paraptosis. In contrast, pretreatment with N-acetylcysteine (NAC) significantly restored cell survival and reduced BIP expression. Our study highlights the potential of DPDS to target two cell death pathways, representing a novel therapeutic strategy for patients with breast cancer resistant to apoptosis-inducing therapies

Methylmercury (MeHg) is a potent neurotoxin that can cross the blood–brain barrier and disrupt neurological function in animals. Emerging evidence suggests that MeHg neurotoxicity may originate from compromised astrocytes, as they are strategically positioned to metabolize and process substances that enter the central nervous system. Thus, a better characterization of the timely cellular responses of astrocytes upon MeHg exposure is key to delineating the toxicology of MeHg. Here, MeHg exposure caused a transient increase in reactive oxygen species (ROS) and intracellular calcium concentration ([Ca²⁺]i), which peaked within 3 h and 30 min, respectively, in astrocytes. Further analyses indicated that the increase in [Ca²⁺]i after MeHg exposure might involve both extracellular Ca²⁺ influx and Ca²⁺ release from intracellular stores, as evidenced by alteration of Ca²⁺ dynamics in cells by targeting specific Ca²⁺ channels with blockers. Further cytotoxicity analyses revealed that antagonizing Ca²⁺‐dependent signaling pathways and ROS levels markedly protected astrocytes against MeHg‐induced cell death. Treatment with lipopolysaccharide improved cell survival under MeHg exposure, suggesting a reciprocal interaction of proinflammatory signaling and MeHg on [Ca²⁺]i kinetics and nitric oxide production. Collectively, our findings indicated that transient alterations in free radical and Ca²⁺ levels in astrocytes may be associated with MeHg‐induced cytotoxicity. Targeting oxidative stress and Ca²⁺ signaling in astrocytes may provide potential strategies for mitigating MeHg‐induced neurotoxicity.

Oral squamous cell carcinoma (OSCC) ranks 16th worldwide as the most common type of malignancy in head and neck cancer globally, and addressing it has been an ongoing but difficult pursuit, as treatment resistance is commonly reported. Hence, employing multiple cell death pathways is an emerging strategy in overcoming treatment resistance in OSCC. We investigate here the effect of heteronemin, a marine sesterterpenoid isolated from sponges, for its anti-cancer potential, hypothesizing that it can induce non-apoptotic cell death pathways to overcome apoptosis-resistant cells and elucidate the underlying mechanisms involved. Our results show that heteronemin significantly kills cancer cells via the induction of the intrinsic apoptotic pathway. It also triggers ferroptosis, down-regulating glutathione peroxidase 4 (GPX4) and upregulating markers of lipid peroxidation such as 4-hydroxynonenal and malondialdehyde. We demonstrate that increasing reactive oxygen species generation plays a central role in triggering these pathways. ensuring the death of the cancer cells despite a compensation attempt via inducing autophagy and modulating Nrf2. Our study is the first to demonstrate the complex but interesting role of heteronemin in killing OSCC cells: inducing apoptosis and switching to ferroptosis as the cells attempt to survive. It also inhibits protective autophagy, leaving OSCC cells incapable of protecting themselves from imminent death. This complex mechanism adds to the existing knowledge on the mechanism of heteronemin as a strong therapeutic compound to treat OSCC cells.

In 2023, a previous study identified a coumarin compound meranzin in the ethanol extract of the edible red macroalga Bangia fuscopurpurea , but only a few studies have investigated the novel bioactivities of this compound and its hydrate. In this study, we examined the potential effects of meranzin and its hydrate on glioblastoma (GBM) using artificial intelligence‐based in silico tools and in vitro models. We used DIGEP‐Pred 2.0 to perform enrichment analysis of proteins affected by the two test compounds in GBM. ADMETlab 3.0 was applied to evaluate their medicinal chemistry properties and to predict absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. We then selected the compound with higher pharmacological potential for in vitro studies in the human GBM cell line. In addition, DIGEP‐Pred 2.0 was used to predict its effects on cancer stemness markers. Enrichment analysis suggested that both meranzin and its hydrate may have therapeutic potential for GBM. Based on the in silico comparisons from ADMETlab 3.0, meranzin hydrate was considered to have higher pharmacological potential. Meranzin hydrate exhibited cytotoxicity in U87 cells, but not in GBM8401 cells. In the U87 model, meranzin hydrate demonstrated anti‐invasion activity (IC ₅₀ = 33.12 μM), although no inhibitory effect on colony formation was observed. Furthermore, meranzin hydrate suppressed the cancer stem cell property of sphere formation (IC ₅₀ = 21.43 μM). Moreover, in silico results showed that meranzin hydrate may downregulate the protein expression of two cancer stemness markers, ALDH1A1 and NANOG, which was further validated by in vitro Western blot analysis. This study provides in silico assessments of the pharmacological potential, together with in vitro evidence of the anti‐malignancy activity of the hydrate of meranzin in a human GBM cell line.

Melanoma is a highly aggressive and heterogeneous form of skin cancer with limited effective treatment options. Although substantial progress has been made in immunotherapy, chemotherapy still serves as an essential alternative therapeutic strategy for many patients. Diphenyl disulfide (DPDS), a small molecule composed of two phenyl groups linked by a disulfide bond, has been reported to exert antioxidant and anticancer activities across several types of malignancies. In this study, we examined the cytotoxic effects of DPDS on melanoma cells and investigated the underlying mechanisms responsible for its antitumor activity. Our results showed that DPDS induces both ferroptosis and apoptosis in melanoma cells in a time-dependent manner. At 24 h, DPDS promoted lipid peroxidation, enhanced xCT ubiquitination, and reduced GPX4 expression, all of which are characteristic hallmarks of ferroptosis. Whereas at 48 h, apoptosis occurred, likely because of NRF2 phosphorylation inhibition, which initially protected against cell death. Additionally, DPDS inhibited the PI3K/AKT/mTOR pathway, leading to decreased mTOR expression and increased autophagy levels. Furthermore, the inhibition of ferroptosis or autophagy partially restored cell viability, suggesting a complex interplay between these pathways in DPDS-induced cytotoxicity. These findings highlight that DPDS may be a potential therapeutic agent for melanoma that functions by leveraging dual programmed cell death mechanisms and targeting the PI3K/AKT/mTOR signaling pathway.

Background Ginger contains many biocompounds, but the antiproliferative effects of its phenylalkanoids (such as 1-(4’-hydroxy-3’-methoxyphenyl)-5-methoxydecan-3-one (HMPM)) on cancer cells are rarely reported. This study aims to explore the antiproliferative effects and mechanisms of HMPM on triple-negative breast cancer (TNBC) cells. Methods ATP-based viability, flow cytometry, and Western blotting were conducted to explore the anti-TNBC in vitro effects and mechanisms. Results HMPM inhibits the proliferation of several breast cancer cell lines. Two TNBC cell lines (Hs578T and MDA-MB-231), showing the highest sensitivity to HMPM, exhibited oxidative stress-dependent antiproliferation, as validated by N-acetylcysteine (NAC). Regarding flow cytometry, HMPM changes cell cycle distribution; upregulates apoptosis (annexin V), reactive oxygen species, and mitochondrial oxidative stress; and downregulates mitochondrial membrane potential and glutathione to a greater extent in TNBC cells than in normal breast cells (H184B5F5/M10), attenuated by NAC. Regarding flow cytometry and Western blotting, HMPM notably triggers oxidative stress-mediated caspase 3 and 8 activation in TNBC cells compared to M10 cells. Finally, HMPM causes oxidative DNA damage, as indicated by γH2AX and 8-hydroxy-2-deoxyguanosine flow cytometry. Conclusion Taken together, the ginger-derived HMPM offers antiproliferative activity against TNBC cells via oxidative stress-dependent changes with limited cytotoxicity to normal cells.

Most chemotherapeutic drugs are introduced to eliminate tumors by targeting apoptotic cell death, but chemoresistance frequently develops owing to the aberrant apoptotic machinery. Although the emergence of immune checkpoint blockade (ICB) has revolutionized cancer therapeutics, poor responses to ICB and an immunosuppressive tumor microenvironment are commonly observed in solid tumors. Hence, restoring chemosensitivity and immunosurveillance is important for improving patient outcomes. Recently, the induction of nonapoptotic programmed cell death (PCD), such as ferroptosis and pyroptosis, has received much attention since these alternative forms of cell death potentially increase chemosensitivity and augment antitumor immunity. Ubiquitination and deubiquitination are well-recognized posttranslational modifications, and the balance between these processes is important for maintaining cellular homeostasis. Dysregulation of deubiquitinating enzymes (DUBs) is reportedly associated with tumor progression. Additionally, emerging studies have suggested the involvement of DUBs in modulating cellular susceptibility to nonapoptotic PCD. Nevertheless, the crosstalk between DUBs and nonapoptotic PCDs and their implications for cancer treatment have not been thoroughly reviewed. In this review, we elucidate the roles of DUBs in regulating ferroptosis and pyroptosis via their DUB activities or noncanonical functions. Moreover, we thoroughly discuss the challenges and urgent problems associated with targeting DUBs to induce nonapoptotic PCDs as cancer therapeutics.

Camptothecin (CPT) derivatives are widely used in cancer therapies, but their efficacy can be attenuated by resistance mechanisms such as autophagy. We recently showed that the aniline compound 4-[4-(4-aminophenoxy)-2,3,5,6-tetrafluorophenoxy] aniline (TFPA) can potently increase CPT cytotoxicity against non-small cell lung cancer (NSCLC) cells. The purpose of this study was to evaluate whether TFPA improves CPT-based chemotherapy by modulating autophagy and other cell death pathways in NSCLC models. Two NSCLC cell lines, A549 and H1299, were tested. The synergism of CPT and TFPA was evaluated by trypan blue exclusion and colony formation assays. Annexin V staining was used for the detection of apoptosis, and autophagy was assessed by acridine orange staining and immunofluorescence. Flow cytometry-based dihydroethidium staining was used to assess oxidative stress. Changes in the expression of apoptosis-associated factors and autophagy-associated factors were determined by Western blot assays. The synergism of CPT and TFPA was validated using a zebrafish xenograft assay. The accumulation of markers for lysosomal expansion (LAMP2) and degradation (cathepsin D) and markers for autophagosome formation (LC3B-II) suggested that blockage of autolysosome formation might impair autophagy in CPT-treated NSCLC cells and subsequently lead to autophagic cell death. Cotreatment with TFPA and CPT induced cell death by increasing the production of reactive oxygen species, which contributed to autophagic impairment and eventually apoptotic cell death in NSCLC cells. Our present work suggests that increased autophagic impairment induced by the combination of CPT and TFPA contributes to the apoptotic cell death of lung cancer cells.