Cancer Cell Death Research Articles

SPOP-mediated RIPK3 destabilization desensitizes LPS/sMAC/zVAD-induced necroptotic cell death.

RIPK1/RIPK3-MLKL signaling molecules are fundamental in initiating necroptotic cell death, but their roles in the development of colon cancer are unclear. This study reports that RIPK3 interacted with SPOP, a component of the E3 ligase within the Cul3 complex. This interaction leads to K48-linked ubiquitination and subsequent proteasomal degradation of RIPK3. Two distinct degron motifs, PETST and SPTST, were identified within the linker domain of RIPK3 for SPOP. RIPK3 phosphorylations at Thr403 by PIM2 and at Thr412/Ser413 by ERK2 are essential to facilitate its interaction with SPOP. Computational docking studies and immunoprecipitation analyses showed that these PIM2 and ERK2 phosphorylations bolster the stability of the RIPK3-SPOP interaction. In particular, mutations of RIPK3 at the degron motifs extended the half-life of RIPK3 by preventing its phosphorylation and subsequent ubiquitination. The deletion of SPOP, which led to increased stability of the RIPK3 protein, intensified LPS/sMAC/zVAD-induced necroptotic cell death in colon cancer cells. These findings underscore the critical role of the SPOP-mediated RIPK3 stability regulation pathway in controlling necroptotic cell death.

Abstract I005: Exploiting the immunoregulatory effect of double-stranded RNAs for cancer therapeutics

Abstract Introns are found in all eukaryotes and are one of the defining characteristics of eukaryotes. After transcription, pre-mRNAs undergo splicing, and introns are excised in the lariat structure. Since excised introns are degraded quickly after debranching, they have been considered as byproducts of gene expression, and their post-splicing role in the cells remains unclear. Here, we find that the inhibition of intron debranching process by depleting a debranching enzyme, DBR1, results in hyperactivation of protein kinase R (PKR) due to accumulation of intron lariat-derived transposable elements (TEs) that can adopt double-stranded secondary structure. Through in vitro PKR-binding assay, we show that PKR strongly binds to intron lariat RNAs harboring TEs, especially inverted Alu repeats. Interestingly, these TE-containing lariat RNAs are retained in the nucleus, but are released to the cytosol during mitosis, where they activate PKR, resulting in aberrant mitotic progression and apoptosis. We further exploit the lariat RNA-PKR interaction during mitosis and show that DBR1 depletion and anti-mitotic chemotherapy drugs can synergistically induce cancer cell death both in vitro and in vivo. Lastly, we perform docking simulation-based screening of DBR1-inhibitory small molecules. Collectively, our findings underscore the significance of intron turnover in avoiding innate immune activation and further suggest a potential strategy to enhance the efficacy of anti-mitotic drugs by targeting intron processing. Citation Format: Keonyong Lee, Jayoung Ku, Tria Asri Widowati, Namwook Kim, Soo Young Park, Han Suk Ryu,Yoosik Kim. Exploiting the immunoregulatory effect of double-stranded RNAs for cancer therapeutics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I005.

Compound 4a induces paraptosis in liver cancer through endoplasmic reticulum stress mediated by the calreticulin protein.

Emerging evidence has highlighted that paraptosis may be an effective strategy for treating liver cancer. In our previous studies, Compound 4a induced paraptosis in cancer cells. Here, the characteristics of Compound 4a-induced paraptosis were further revealed and, for the first time, the target and related molecular mechanisms of Compound 4a-induced paraptosis in liver cancer were defined. The effects and mechanism of Compound 4a in liver cancer cells were studied in in vitro and in vivo (BALB/c-nude xenograft model) experiments, and the targets of Compound 4a that trigger paraptosis were identified and confirmed via mass spectrometry-based drug affinity responsive target stability (DARTS) analyses, siRNA experiments and a cellular thermal shift assay (CETSA). The function and distribution of calreticulin (CRT) protein were detected via Cal-520 AM and immunofluorescence staining, respectively. Compound 4a effectively induced paraptosis-like cell death in liver cancer, both in vitro and in vivo, and its effect was comparable with the first-line anti-liver cancer drug oxaliplatin but with a higher safety profile. We identified the CRT protein as a target of Compound 4a, which caused cellular endoplasmic reticulum stress (ERS) and calcium overload. CRT knockdown weakened the anti-liver cancer activity of Compound 4a, which may be related to the inhibition of paraptosis. Compound 4a represents a potentially safe and effective agent for the treatment of liver cancer. The characteristics of Compound 4a-triggered paraptosis was clarified and a unique function of CRT in paraptosis was revealed.

Nanoconjugate Carrying pH-Responsive Transferrin Receptor-Targeted Hesperetin Triggers Triple-Negative Breast Cancer Cell Death through Oxidative Attack and Assemblage of Pro-Apoptotic Proteins.

Triple-negative breast cancer (TNBC) is recognized as a major aggressive subtype of breast cancer due to its expeditious worsening growth, extensive metastatic capability, and recalcitrance to standard current treatments. Hesperetin (HSP), a natural bioflavonoid from citrus fruits, demonstrates pronounced anticancer efficacy, but its hydrophobicity limits its clinical development. The present study reports the fabrication of a biocompatible and pH-responsive transferrin (TF) receptor-targeted HSP-loaded poly(lactic-co-glycolic acid) (PLGA) nanobioconjugate (PLGA-HSP-TF NPs) and the exploration of its in vitro and in vivo antineoplastic potential. PLGA nanoparticles (NPs), PLGA-HSP NPs, and PLGA-HSP-TF NPs were synthesized and characterized by DLS, FTIR, FE-SEM, and 1H NMR spectroscopy. The stability and in vitro release profile of nanoparticles were inspected, and anticancer efficacy was scrutinized in terms of in vitro cytotoxicity, oxidative stress and apoptosis biomarkers, and cell cycle arrest. In vivo tumor regression and host survival studies were executed in Ehrlich ascites carcinoma (EAC) cell-bearing Swiss albino mice. The drug uptake of highly stable PLGA-HSP-TF NPs was accomplished effectively in MDA-MB-231 cells and showed the pH-dependent intracellular release of HSP, which generated excessive intracellular reactive oxygen species (ROS) that led to oxidative assault to the TNBC cells. This elevated ROS dropped the mitochondrial membrane potential and triggered apoptosis-mediated cell death by arresting the cell cycle at the G0/G1 phase. Furthermore, PLGA-HSP-TF NPs unveiled significant in vivo Ehrlich ascites carcinoma regression and host survival compared to free HSP with minimum toxicity at a minimum dose of 20 mg/kg body weight. The study divulges that PLGA-HSP-TF NPs may be an astounding anticancer nanocandidate for aggressive triple-negative breast cancer therapy.

A Rationally Designed Azobenzene Photoswitch for DNA G‐Quadruplex Regulation in Live Cells

AbstractG‐quadruplex (G4) DNA structures are increasingly acknowledged as promising targets in cancer research, and the development of G4‐specific stabilizing compounds may lay a fundamental foundation in precision medicine for cancer treatment. Here, we propose a light‐responsive G4‐binder for precise modulation of drug activation, providing dynamic and spatiotemporal control over G4‐associated biological processes contributing to cancer cell death. We developed a specialized fluorinated azobenzene (AB) switch equipped with a quinoline unit and a positively charged carboxamide side chain, Q‐Azo4F‐C, designed for targeted binding to G4 structures within cells. Biophysical studies, combined with molecular dynamics simulations, provide insights into the unique coordination modes of the photoswitchable ligand in its trans and cis configurations when interacting with G4s. The observed variations in complexation processes between the two isomeric states in different cancer cell lines manifest in more than 25‐fold reversible cytotoxic activity. Immunostaining conducted with the structure‐specific G4 antibody (BG4), establishes a direct correlation between cytotoxicity and the varying extent of G4 induction regulated by the two isoforms. Finally, we demonstrate the photo‐driven reversible regulation of G4 structures in lung cancer cells by Q‐Azo4F‐C. Our findings highlight the potential of light‐responsive G4‐binders in advancing precision cancer therapy through dynamic control of G4‐mediated pathways.

Recent Advances in Nanomaterial-Mediated Cell Death for Cancer Therapy.

Nanomedicine has shown great anticancer potential by disrupting redox homeostasis and increasing the levels of oxidative stress, but the therapeutic effect is limited by factors including the intrinsic self-protection mechanism of tumors. Cancer cell death can be induced by the exploration of different cell death mechanisms, such as apoptosis, pyroptosis, necroptosis, cuproptosis, and ferroptosis. The merging of nanotechnology with biomedicine has provided tremendous opportunities to construct cell death-based nanomedicine for innovative cancer therapy. Nanocarriers are not only used for the targeted delivery of cell death inducers, but also as therapeutic components to induce cell death to achieve efficient tumor treatment. This review focuses on seven cell death modalities mediated by nanomaterials, such as apoptosis, pyroptosis, necroptosis, ferroptosis, cuprotosis, immunogenic cell death, and autophagy. The mechanisms of these seven cell death modalities are described in detail, as well as the preparation of nanomaterials that induce them and the mechanisms, they used to exert their effects. Finally, this work describes the potential future development based on the current knowledge related to cell death induced by nanomaterials.

TMEM206 Contributes to Cancer Hallmark Functions in Colorectal Cancer Cells and Is Regulated by p53 in a p21-Dependent Manner

Acid-induced ion flux plays a role in pathologies where tissue acidification is prevalent, including cancer. In 2019, TMEM206 was identified as the molecular component of acid-induced chloride flux. Localizing to the plasma membrane, TMEM206 contributes to cellular processes like acid-induced cell death. Since over 50% of human cancers carry loss of function mutations in the p53 gene, we aimed to analyze how TMEM206 is regulated by p53 and its role in cancer hallmark function and acid-induced cell death in HCT116 colorectal cancer (CRC) cells. We generated p53-deficient HCT116 cells and assessed TMEM206-mediated Cl− currents and transcriptional regulation using the patch-clamp and a dual-luciferase reporter assay, respectively. To investigate the contribution of TMEM206 to cancer hallmark functions, we performed migration and metabolic activity assays. The role of TMEM206 in p53-mediated acid-induced cell death was assessed with cell death assays. The TMEM206 mRNA level was significantly elevated in human primary CRC tumors. TMEM206 knockout increased acid-induced cell death and reduced proliferation and migration, indicating a role for TMEM206 in these cancer hallmark functions. Furthermore, we observed increased TMEM206 mRNA levels and currents in HCT116 p53 knockout cells. This phenotype can be rescued by transient overexpression of p53 but not by overexpression of dysfunctional p53. In addition, our data suggest that TMEM206 may mediate cancer hallmark functions within p53-associated pathways. TMEM206 promoter activity is not altered by p53 overexpression. Conversely, knockout of p21, a major target gene of p53, increased TMEM206-mediated currents, suggesting expression control of TMEM206 by p21 downstream signaling. Our results show that in colorectal cancer cells, TMEM206 expression is elevated, contributes to cancer hallmark functions, and its regulation is dependent on p53 through a p21-dependent mechanism.

Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer: A Plausible Alliance to Enhance Cell Death

Background/Objectives: Head and neck cancer (HNC) is among the most common cancer types globally, with its incidence expected to increase significantly in the coming years. Oral squamous cell carcinoma (OSCC), the predominant subtype, exhibits significant heterogeneity and resistance to treatment. Current therapies, including surgery, radiation, and chemotherapy, often result in poor outcomes for advanced stages. Cetuximab, an EGFR inhibitor, is widely used but faces limitations. This study explores the combined inhibition of EGFR and mitotic proteins to enhance treatment efficacy. Methods: We analyzed the effects of co-treating OSCC cells with small molecules targeting MPS-1 (BAY1217389), Aurora-B (Barasertib), or KSP (Ispinesib), alongside Cetuximab. The rationale is based on targeting EGFR-mediated survival pathways and the mitotic checkpoint, addressing multiple cell cycle phases and reducing resistance. Results: Our findings indicate that inhibiting MPS-1, Aurora-B, or KSP enhances Cetuximab’s therapeutic potential, promoting increased cancer cell death. Additionally, we examined EGFR, MPS-1, Aurora-B, and KSP expression in OSCC patient samples, revealing their clinicopathologic significance. Conclusions: This combinatorial approach suggests a promising strategy to improve treatment outcomes in OSCC.

Targeting Lysosomal Thiols for Immunogenic Cancer Cell Death

The number and stability of lysosomes (LYs) are different in cancer and healthy cells that makes them a possible target for cancer specific therapy. However, no LY‐targeting drug is clinically approved yet. We describe in this paper a new therapeutic approach based on alkylation of lysosomal thiols in cancer cells by reversible thiol binder 11. The treatment with 11 increases the level of lysosomal reactive oxygen species leading to their destabilization, disruption and immunogenic cancer cell death. These effects are not observed in healthy cells. In murine sarcoma Nemeth‐Kellner (NK)/Ly‐RB model, 11 exhibits the spectacular therapeutic effect: it extends the lifespan of the treated mice from 21 to 85 days and cures 40% of mice. The survived mice develop antibodies against tumor NK/Ly‐RB cells. Their repeated challenge with the NK/Ly‐RB cells results in 100% mice survival compared to 0% survival in the control group of naïve mice. Ex vivo data indicate that neutrophils in spleen of the cured animals are also involved in targeting cancer cells and produce neutrophil extracellular traps. In summary, 11 induces the direct antitumor effect supported by humoral immune responses, as well as priming neutrophil’s reaction against tumors.

Targeting Lysosomal Thiols for Immunogenic Cancer Cell Death.

The number and stability of lysosomes (LYs) are different in cancer and healthy cells that makes them a possible target for cancer specific therapy. However, no LY-targeting drug is clinically approved yet. We describe in this paper a new therapeutic approach based on alkylation of lysosomal thiols in cancer cells by reversible thiol binder 11. The treatment with 11 increases the level of lysosomal reactive oxygen species leading to their destabilization, disruption and immunogenic cancer cell death. These effects are not observed in healthy cells. In murine sarcoma Nemeth-Kellner (NK)/Ly-RB model, 11 exhibits the spectacular therapeutic effect: it extends the lifespan of the treated mice from 21 to 85 days and cures 40% of mice. The survived mice develop antibodies against tumor NK/Ly-RB cells. Their repeated challenge with the NK/Ly-RB cells results in 100% mice survival compared to 0% survival in the control group of naïve mice. Ex vivo data indicate that neutrophils in spleen of the cured animals are also involved in targeting cancer cells and produce neutrophil extracellular traps. In summary, 11 induces the direct antitumor effect supported by humoral immune responses, as well as priming neutrophil's reaction against tumors.

Single-agent Adavosertib Shows Anticancer Effects Against Colorectal Cancer Cells.

Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related deaths worldwide. Adavosertib (AZD1775), a small molecule inhibitor of WEE1 kinase, abrogates G2/M cell cycle arrest and induces double-stranded DNA breaks. According to previous findings, adavosertib, in combination with other DNA-damaging agents, causes premature mitosis and cell death in p53-mutated cancer cells mainly via abrogation of the G2/M cell cycle checkpoint. This study aims to evaluate the inhibition of WEE1 kinase by adavosertib as monotherapy in the TP53-wildtype human CRC cell line HCT116. In this study, HCT116 cells were treated with different concentrations of adavosertib for 24 to 72 hours. Cell viability was assessed by Water-Soluble Tetrazolium 1 (WST-1) assay and crystal violet assays. Cell migration was evaluated by the wound healing assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The IC50 value of adavosertib for the HCT116 cell line was 0.1310 μM. Adavosertib monotherapy (both 0.125 and 0.250 μM) significantly reduced cell viability, inhibited cell migration and abrogated intra-S phase cell cycle arrest. In addition, 0.250 μM of adavosertib significantly induced apoptosis in HCT116 cells. Adavosertib effectively inhibits the TP53-wildtype HCT116 cells via the abrogation of intra-S phase cell cycle arrest. Our findings suggest that adavosertib monotherapy may be a potential targeted therapy for CRC.

The RIP3 activator C8 regulates the autophagy flux mediated by p62 and promotes the immunogenic form of cell death in human gastric cancer cells

The RIP3 activator C8 regulates the autophagy flux mediated by p62 and promotes the immunogenic form of cell death in human gastric cancer cells

Prolonged glutamine starvation reactivates mTOR to inhibit autophagy and initiate autophagic lysosome reformation to maintain cell viability.

Autophagy, a cellular recycling mechanism, utilizes lysosomes for cellular degradation. Prolonged autophagy reduces the pool of functional lysosomes in the cell. However, lysosomal homeostasis is maintained through the regeneration of functional lysosomes during the terminal stage of autophagy, i.e. Autophagic lysosome reformation (ALR). Through confocal microscopy during glutamine starvation, we unravel the regeneration of tubules from autolysosomes by undertaking significant membrane remodeling, which majorly depends on mTOR reactivation, RAB7 dissociation, phosphatidyl inositol 3 phosphate (PI3P) dependent dynamin 2 and clathrin recruitment. In glutamine-starved cells, we found mTOR is the central modulator in regulating ALR initiation, and its pharmacological inhibition with rapamycin leads to a decrease in lysosomal tubulation. Moreover, RAB7 and Clathrin are essential for tubule elongation and it showed that siRNA targeting RAB7 and Clathrin restricts tubule initiation under glutamine starvation. In this setting, we examined the physiological relevance of ALR during prolonged glutamine deprivation and found that genetic and pharmacological inhibition of critical proteins involved in ALR promotes cell death in oral cancer cells, establishing ALR is essential for maintaining cell survival during stress.

The interplay between cell death and senescence in cancer

The interplay between cell death and senescence in cancer

Trichosanthin elicits antitumor activity via MICU3 mediated mitochondria calcium influx

IntroductionTrichosanthin (TK) is a glycoprotein extracted from the Chinese medicinal herb Trichosanthes kirilowi, which has anti-virus and anti-tumor activity. However, the target and detailed mechanism of TK remains elusive. ObjectivesWe aimed to identify novel antitumor targets of TK in lung adenocarcinoma and study its anti-tumor mechanism. MethodsWe utilized a Lewis lung carcinoma mouse model to evaluate the inhibition of TK on tumor growth. CCK8 assay was utilized to calculate IC50 of trichosanthin on A549 and H1299. In-vitro cellular assays and in-vivo xenograft mice studies were used to investigate MICU3 overexpression and TK treatment on tumor growth. Fluo-4 dye and JC-1 staining was used to measure the mitochondrial calcium levels and membrane potential. H&E and immunohistochemistry staining were applied the asses the effect of TK on tumor and microenvironment. RNA sequencing was applied to analyze transcriptome changes in TK-treated and MICU3-overexpressed tumor cells. The influence of trichosanthin on DNMT3B expression and MICU3 methylation were detected by qPCR and Western blotting. Transcriptional activity of the MICU3 gene was measured by ChIP-PCR and luciferase assays. ResultsTrichosanthin ihibited the tumor growth in vivo, resulting cancer cell growth inhibition and cell death, with almost no effect on normal cells. IC50 of trichosanthin in A549 and H1299 cells were 62.8 μg/ml and 39.7 μg/ml, respectively. Mitochondrial Calcium Uptake Family complex MICU3 was shown to associated with favorable prognosis and was upregulated upon trichosanthin treatment, along with reduces tumor cell growth and migration, and increased cell death both in vitro and in vivo. Increased mitochondrial calcium level was observed in MICU3 overexpression cells. Pathway analysis of RNA-seq data revealed that cytokine and receptor pathways were enriched in MICU3-overexpressing cells. Trichosanthin decreased DNMT3B expression and altered MICU3 methylation while increased FOSL2 expression and reduced methylation that correlated with increased transcription of the MICU3 gene. ConclusionTrichosanthin elicits antitumor activity in lung adenocarcinoma via repressing DNMT3B and increasing FOSL2, which in turn induces MICU3-mediated mitochondrial calcium influx and tumor cell death.

Exploring structure-directed immunogenic cytotoxicity of arginine-rich peptides for cytolysis-induced immunotherapy of cancer

The same cells can die with varied immunological consequences. For the purpose of cancer therapy, stronger immunogenic death of cancer cells is considered favorable. Membrane disruptive peptides are cytotoxic agents with tunable structures capable of not just killing heterogeneous cancer cells, but also inducing immunogenic death. However, the chemo-structural principles that underlie their immunogenic cytotoxicity remain elusive. Here we investigated a series of arginine-rich amphipathic peptides with representative structures on the relationship between the mode of cell death and the immunogenic potency. Among several hydrophobic motif-appended cyclic octaarginine peptides, FC-14 was found to induce cell stress and necroptotic death, unlike apoptotic peptide RL2 and membrane-dissolving peptide RL1. Their differing abilities to release immunogenic death markers correlated well with their potential to activate innate immunity and protective vaccinal effect in a prophylactic model, with FC-14 being the most potent. FC-14 can be pre-opsonized with albumin into nanoparticles (PopAN-FC-14) using PopAN technology to improve its pharmacokinetic properties for intravenous injection. In a syngeneic mouse model of subcutaneous breast cancer, PopAN-FC-14 showed superior therapeutic effect and safety profile than the albumin formulated nanomedicine Nab-paclitaxel (Nab-PTX). Boost injections of PopAN-FC-14 significantly enhanced tumor-specific cellular and humoral immunities, acting similarly as in-situ cancer vaccine. Overall, this work demonstrates a novel focus on the immunogenic cytotoxicity of peptides and a practical approach for effective systemic therapy of cancer.

Immunogenic properties of nickel-doped maghemite nanoparticles and the implication for cancer immunotherapy

Nanoparticles are commonly used in diagnostics and therapy. They are also increasingly being implemented in cancer immunotherapy because of their ability to deliver drugs and modulate the immune system. However, the effect of nanoparticles on immune cells involved in the anti-tumor immune response is not well understood. The study reported here showed that nickel-doped maghemite nanoparticles (FN NP) are differentially cytotoxic to cultured mouse and human cancer cell lines, causing their death without negatively impacting the subsequent anticancer immune response. It also found that FN NP induced cell death in the mouse colorectal cancer cell line CT26 and human prostate cancer cell line PC-3, but not in the human prostate cancer cell line LNCaP. The induced cancer cell death did not affect the phenotype and responsivity of the isolated mouse peritoneal macrophages, or ex vivo-generated mouse bone marrow-derived, or human monocyte-derived dendritic cells. Additionally, the induced cancer cell death did not prevent the ex vivo-generated mouse or human dendritic cells from stimulating lymphocytes and enriching cell cultures with cancer cell-reactive T-cells. In conclusion, this study shows that FN NP could be a valuable platform for targeting cancer cells without causing immunosuppressive effects on the subsequent anticancer immune response.

Synthesis, Characterisation, Single Crystal Structure and Evaluation of a Redox Innocent Carbazate Functionalized Phenanthroline for Antimycobacterial and Anticancer Activity

Development of bioactive candidates for cancer and bacterial infections are ever demanding challenges due to the resistance shown by these cancer and bacterial cells for already exposed drug molecules. Methyl carbazate derivatized phenanthroline compound 6-[2-(methoxycarbonyl)diazen-1-yl]-1,10-phenanthroline-5-one (MCDPO) is synthesized in a three step reaction from 1,10-phenanthroline. The spectroscopic features of MCDPO are studied by HRMS, IR, 1H NMR and 13C NMR, UV-visible spectroscopy. The three-dimensional molecular structure of the MCDPO is confirmed by single crystal XRD study. The MCDPO crystallized in a triclinic system P-1 space group with the following unit cell parameter: a=5.0347(2) Å, b=10.3509(4) Å, c=11.8816(4) Å, α=84.431(3)°, β=84.172(3)°, γ=81.380(4)°, and V=606.92(4) Å3 at T=133 K. The MCDPO is containing aromatic rings, hydrogen bonding donors as well as hydrogen bonding acceptor groups forming supramolecular molecular arrangements through C-H···O, C-H···N, C-O···C, π-π and π···C non-covalent interactions. Electrochemical redox and electrochromic features of MCDPO are studied through cyclic voltammetry and UV-vis based spectroelectrochemistry. This compound shows good anticancer activity with IC50 values 1.438, 6.576 and 2.901 µM against 4T1, MCF-7 and PC-3 cancer cell lines respectively. The flow cytometry study on 4T1 cells suggests that the MCDPO promoted cancer cell death by inducing apoptosis, and cell cycle arrest in the G0/G1 phase. It also induces nuclear fragmentation and reactive oxygen species (ROS) generation, which was studied by DAPI, AO, and DCFH-DA based cellular staining studies by fluorescence confocal imaging. The MCDPO also studied for antibacterial activity against Escherichia Coil bacteria and Mycobacterium tuberculosis (Mtb). The MCDPO shows minimum inhibitory concentration (MIC) of 0.39 µg/mL against Mtb which is slightly better than the one of the clinically used drug candidates Ethambutol.

The intricate interplay between ferroptosis and efferocytosis in cancer: unraveling novel insights and therapeutic opportunities.

The complex interplay between ferroptosis and efferocytosis in cancer has attracted significant interest recently. Efferocytosis, the process of eliminating apoptotic cells, is essential for preserving tissue homeostasis and reducing inflammation. However, dysregulation of efferocytosis can have profound effects on cancer. Apoptotic cells accumulate because of impaired efferocytosis, which triggers chronic inflammation and the release of pro-inflammatory chemicals. Surprisingly, accumulating evidence suggests that dysregulation of ferroptosis- a form of controlled cell death characterized by lipid peroxidation and the buildup iron-dependent reactive oxygen species (ROS)-can influence efferocytic activities within the tumor microenvironment. Dysfunctional iron metabolism and increased lipid peroxidation, are associated with ferroptosis, resulting in inadequate apoptotic cell clearance. Conversely, apoptotic cells can activate ferroptotic pathways, increasing oxidative stress and inducing cell death in cancer cells. This reciprocal interaction emphasizes the complex relationship between efferocytosis and ferroptosis in cancer biology. Understanding and managing the delicate balance between cell clearance and cell death pathways holds significant therapeutic potential in cancer treatment. Targeting the efferocytosis and ferroptosis pathways may offer new opportunities for improving tumor clearance, reducing inflammation, and sensitizing cancer cells to therapeutic interventions. Further research into the interaction between efferocytosis and ferroptosis in cancer will provide valuable insights for the development of novel therapies aimed at restoring tissue homeostasis and improving patient outcomes.

Demystifying the management of cancer through smart nano-biomedicine via regulation of reactive oxygen species.

Advancements in therapeutic strategies and combinatorial approaches for cancer management have led to the majority of cancers in the initial stages to be regarded as treatable and curable. However, certain high-grade cancers in the initial stages are still regarded as chronic and difficult to manage, requiring novel therapeutic strategies. In this era of targeted and precision therapy, novel strategies for targeted delivery of drug and synergistic therapies, integrating nanotherapeutics, polymeric materials, and modulation of the tumor microenvironment are being developed. One such strategy is the study and utilization of smart-nano biomedicine, which refers to stimuli-responsive polymeric materials integrated with the anti-cancer drug that can modulate the reactive oxygen species (ROS) in the tumor microenvironment or can be ROS responsive for the mitigation as well as management of various cancers. The article explores in detail the ROS, its types, and sources; the antioxidant system, including scavengers and their role in cancer; the ROS-responsive targeted polymeric materials, including synergistic therapies for the treatment of cancer via modulating the ROS in the tumor microenvironment, involving therapeutic strategies promoting cancer cell death; and the current landscape and future prospects.