Inhibited Cell Survival Research Articles

SOCS2 inhibits the tumorigenesis of GISTs and increases the sensitivity of GISTs to imatinib by suppression of KIT activation

The suppressors of cytokine signaling 2 (SOCS2) inhibits growth hormone receptor (GHR) signaling by negative feedback in the regulation of metabolism. In this study, we found that GHR upregulates SOCS2 expression, whereas KIT mutations, the key driver mutations of gastrointestinal stromal tumors (GISTs), inhibits SOCS2 expression in GISTs. Furthermore, SOCS2 associated and inhibited the activation of KIT mutations, but not wild-type KIT, in addition to its inhibition of GHR signaling, suggesting that KIT mutations may promote their activation by downregulation of SOCS2 expression. Accordingly, SOCS2 inhibited GIST cell survival and proliferation in vitro. In KITV558A/WT mice, knockout of SOCS2 expression increased the tumorigenesis of GISTs and decreased the life span of the mice. In addition, the presence of SOCS2 increased the inhibition of KIT signaling and GIST cell survival and proliferation by imatinib in vitro, and imatinib treatment further reduced tumor growth in KITV558A/WT mice compared with that in KITV558A/WT/SOCS2-/- mice, indicating the key role of SOCS2 in the sensitivity of GISTs to the targeted therapy. Taken together, our data revealed the key role of SOCS2 in the tumorigenesis of GISTs and the sensitivity of GISTs to the targeted therapy, providing a better basis for the improved treatment strategy.

Discovery and Optimization of a Series of Novel Morpholine-Containing USP1 Inhibitors.

Ubiquitin-specific protease 1 (USP1), a well-known member of the deubiquitinating enzymes, serves as a key regulator in DNA damage repair (DDR) processes. Herein, we utilized ring-opening and cyclization strategies based on KSQ-4279 to design a novel series of USP1 inhibitors featuring a morpholine scaffold. Notably, compound 38-P2 exhibited a more potent enzymatic and cellular inhibition activity compared to KSQ-4279. Mechanistically, 38-P2 was characterized as a selective, reversible, and noncompetitive USP1 inhibitor. 38-P2 efficiently activated the DDR pathway, induced cell cycle arrest and cell apoptosis, and inhibited cell survival. Importantly, it enhanced the sensitivity of olaparib-resistant cells to olaparib and showed a synergetic effect with andrographolide in BRCA-proficient cancer cells. Furthermore, 38-P2 had favorable pharmacokinetic profiles and good safety properties in vitro and in vivo. In the MDA-MB-436 xenograft model, 38-P2 displayed significant, dose-dependent antitumor efficacy. Overall, these findings indicate that 38-P2 is a promising lead compound for further drug development.

Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer

Hyperactive c-Met signaling pathway caused by altered MET is a common mechanism underlying gastric cancer and represents an attractive target for the treatment of gastric cancer with MET alterations. However, no c-Met kinase inhibitors are currently approved specifically for the treatment of c-Met-amplified gastric cancer. Recently, bozitinib, a highly selective c-Met kinase inhibitor, has shown remarkable potency in selectively inhibiting MET-altered non-small cell lung cancer and secondary glioblastoma. In this study, we investigate the antitumor activity of bozitinib against MET-amplified gastric cancer and elucidate its molecular mechanism. Bozitinib demonstrates a strong effect on MET-amplified gastric cancer cells by blocking the c-Met signaling pathway, leading to the inhibition of cell proliferation and survival, as well as the induction of G0/G1 phase arrest and apoptosis. Structurally, bozitinib is optimally embedded in the ATP pocket of c-Met and firmly binds via an extensive interaction network. In addition, bozitinib efficiently inhibits c-Met resistance-conferring mutations G1163R and Y1230H, although its potency is significantly decreased against the D1228N and Y1230C mutations. Overall, our study reveals the molecular mechanism of bozitinib against c-Met, highlights its ability to overcome acquired resistance mutations, and provides valuable insights into further design and improvement of selective c-Met inhibitors.

3D Mechanical Response Stem Cell Complex Repairs Spinal Cord Injury by Promoting Neurogenesis and Regulating Tissue Homeostasis.

Spinal cord injury (SCI) leads to acute tissue damage that disrupts the microenvironmental homeostasis of the spinal cord, inhibiting cell survival and function, and thereby undermining treatment efficacy. Traditional stem cell therapies have limited success in SCI, due to the difficulties in maintaining cell survival and inducing sustained differentiation into neural lineages. A new solution may arise from controlling the fate of stem cells by creating an appropriate mechanical microenvironment. In this study, mechanical response stem cell complex (MRSCC) is created as an innovative therapeutic strategy for SCI, utilizing 3D bioprinting technology and gelatin microcarriers (GM) loaded with mesenchymal stem cells (MSCs). GM creates an optimal microenvironment for MSCs growth and paracrine activity. Meanwhile, 3D bioprinting allows accurate control of spatial pore architecture and mechanical characteristics of the cell construct to encourage neuroregeneration. The mechanical microenvironment created by MRSCC is found to activate the Piezo1 channel and prevent excessive nuclear translocation of YAP, thereby increasing neural-related gene expression in MSCs. Transplanting MRSCC in rats with spinal cord injuries boosts sensory and motor recovery, reduces inflammation, and stimulates the regeneration of neurons and glial cells. The MRSCC offers a new tissue engineering solution that can promote spinal cord repair.

Bola-Amphiphilic Dendrimer Enhances Imatinib to Target Metastatic Ovarian Cancer via β-Catenin-HRP2 Signaling Axis.

Ovarian cancer is the leading cause of death among all gynecological malignancies, and drug resistance renders the current chemotherapy agents ineffective for patients with advanced metastatic tumors. We report an effective treatment strategy for targeting metastatic ovarian cancer involving a nanoformulation (Bola/IM)─bola-amphiphilic dendrimer (Bola)-encapsulated imatinib (IM)─to target the critical mediator of ovarian cancer stem cells (CSCs) CD117 (c-Kit). Bola/IM offered significantly more effective targeting of CSCs compared to IM alone, through a novel and tumor-specific β-catenin/HRP2 axis, allowing potent inhibition of cancer cell survival, stemness, and metastasis in metastatic and drug-resistant ovarian cancer cells. Promising results were also obtained in clinically relevant patient-derived ascites and organoids alongside high tumor-oriented accumulation and favorable pharmacokinetic properties in mouse models. Furthermore, Bola/IM displayed synergistic anticancer activity when combined with the first-line chemotherapeutic drug cisplatin in patient-derived xenograft mouse models without any adverse effects. Our findings support the use of Bola/IM as a nanoformulation to empower IM, providing targeted and potent treatment of metastatic ovarian cancer. Our study thus represents a significant advancement toward addressing the unmet medical need for improved therapies targeting this challenging disease.

GRHL3 drives radiotherapy resistance and blocks the anti-tumor response of NK and CD4+ T cells in lung squamous cell carcinoma via RNF2.

Grainyhead-like protein 3 homolog (GRHL3) has been identified as a top transcription factor associated with keratinization in lung squamous cell carcinoma (LUSC). We designed this study to elucidate the function of GRHL3 in radioresistance in LUSC and the mechanism involved. Transcriptome differences between radioresistant and parental cells were analyzed to identify the hub transcription factor. GRHL3 expression was overexpressed in radioresistant cells relative to parental cells, and the knockdown of GRHL3 conferred sensitivity to radioresistant LUSC cells, induced DNA damage, inhibited cell survival, and reduced tumor load in mice. GRHL3 promoted ring finger protein 2 (RNF2) transcription by binding to the RNF2 promoter. GRHL3 induced a radioresistant phenotype in parental cells and led to compromised anti-tumor immune responses of CD4+ T cells and NK cells. The GRHL3-promoted tumor progression was reversed by the knockdown of RNF2. The DNA methylation of GRHL3 was reduced in radioresistant cells. All in all, as GRHL3, helps LUSC cells escape from the immune surveillance and mediates radioresistance, it might be an attractive target for therapy-resistant LUSC.

LCP1 promotes ovarian cancer cell resistance to olaparib by activating the JAK2/STAT3 signalling pathway

ABSTRACT Background Resistance to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) remain a major challenge in ovarian cancer (OC) treatment. However, the underlying mechanism of PARPi resistance is still poorly characterized. Increasing evidence has proven that lymphocyte cytosolic protein 1 (LCP1) promotes tumor progression. The JAK2/STAT3 signaling pathway plays an important role in increasing tumor metastatic ability and chemoresistance in cancer by promoting epithelial – mesenchymal transition (EMT). Methods We established an olaparib-resistant OC cell line and studied its toxicologic effects through cell survival, Transwell, colony formation, western blotting and flow cytometry assays. RNA sequencing and screening were then performed to identify genes associated with olaparib resistance. Lymphocyte cytosolic protein 1 (LCP1) was found to be overexpressed in olaparib-resistant OC cells. Results The inhibition of cell survival and promotion of cell apoptosis induced by olaparib in parental cells were significantly attenuated in olaparib-resistant cells. LCP1 was upregulated in olaparib-resistant cells compared with parental OC cells. Moreover, we found that the protein levels of JAK2/STAT3 signaling pathway components and EMT markers were increased in olaparib-resistant cells. Overexpression of LCP1 increased olaparib resistance in OC cells, and knockdown of LCP1 attenuated olaparib resistance. The changes in the protein levels of JAK2/STAT3 signaling pathway members and EMT markers between the cell types were similar to the changes in the levels of LCP1. Conclusions These findings indicate that LCP1 expression may play an important role in the resistance of OC to olaparib by activating the JAK2/STAT3 signaling pathway and EMT. LCP1 could be a potential therapeutic target for patients with OC who are resistant to olaparib. Our study provides a new mechanism of olaparib resistance.

Ruta graveolens, but Not Rutin, Inhibits Survival, Migration, Invasion, and Vasculogenic Mimicry of Glioblastoma Cells.

Glioblastoma (GBM) is the most aggressive type of brain tumor, characterized by poor outcome and limited therapeutic options. During tumor progression, GBM may undergo the process of vasculogenic mimicry (VM), consisting of the formation of vascular-like structures which further promote tumor aggressiveness and malignancy. The resulting resistance to anti-angiogenetic therapies urges the identification of new compounds targeting VM. Extracts of natural plants may represent potential therapeutic tools. Among these, components of Ruta graveolens water extract (RGWE) display a wide range of biological activities. To test the effect of RGWE on human GBM and rat glioma cell line VM, tube formation on a gelled matrix was monitored. Quantitative assessment of VM formation shows the clear-cut inhibitory activity of RGWE. Unlike rutin, one of the most abundant extract components, the whole RGWE strongly reduced the migration and invasion of GBM tumor cells. Moreover, RGWE induced cell death of GBM patient-derived cancer stem cells and impaired VM at sub-lethal doses. Overall, our data reveal a marked RGWE-dependent inhibition of GBM cell survival, migration, invasion, and VM formation. Thus, the clear-cut ability of RGWE to counteract GBM malignancy deserves attention, holding the promise to bring natural products to clinical use, thus uncovering new therapeutic opportunities.

Gene Expression Profiling of Maslinic Acid-treated MCF-7 Breast Cancer Cells Using Nanostring nCounter Pancancer Pathway Panel

Breast cancer remains a significant global health concern, impacting millions of women every year. Maslinic acid (MA), a pentacyclic triterpene has been found to exert promising anticancer effect in various cancers, including breast cancer, yet the underlying mechanisms remain unclear. This study aims to elucidate the anticancer properties of MA via gene expression profiles in breast cancer cells. Cytotoxicity assay results revealed that MCF-7 exerts the highest sensitivity after 72 h of MA treatment followed by T-47D and MDA-MB-231. MCF-7 were then selected for in-depth analysis using the Nanostring nCounter Pancancer Pathway Panel to analyze the differential expression of genes (DEGs). Across three time points (24, 48, and 72 h), 20 significant DEGs were identified, of which 5 were upregulated and 15 were downregulated. In silico analysis indicated that these DEGs were involved in Pathway of Cancer, Focal Adhesion-PI3K-mTOR Signaling Pathway, PI3K-Akt, and Ras Signaling Pathway. The regulation of these DEGs contributes to several cellular activities such as apoptosis, inhibition of cell proliferation, cell cycle and survival, reduction of glycolysis, angiogenesis, and DNA repair. Additionally, the unfolded protein response emerged as a noteworthy biological process in this study. This study unravels the molecular mechanisms underpinning the therapeutic potential of MA against breast cancer.

Gochujang suppresses cell survival and changes reactive oxygen species metabolism in colorectal cancer cells.

There is a significant global increase in colorectal cancer (CRC) among young adults. Gochujang, one of the signature Korean traditional fermented foods, contains various bioactive compounds and has multiple health-beneficial effects, including anticancer effects; however, the detailed cellular and molecular mechanisms of its anticancer outcomes are not fully understood. The objective of the present study was to investigate the detailed underlying anticancer mechanisms of Gochujang in CRC cells. Gochujang was extracted with 80% ethanol, and total polyphenol contents (9.9 ± 1.63 mgGAE/g) and total flavonoid contents (0.14 ± 0.07 mgQE/g) of Gochujang extract (GE) were evaluated. GE significantly suppressed cell viability, migration, and colony formation in CRC cells. Also, GE increased the cell cycle arrest-related protein p21 level, whereas it decreased cell cycle progression-associated proteins, such as p-Rb. Moreover, GE markedly elevated the levels of proapoptotic proteins (e.g. Bim and c-PARP), while it downregulated antiapoptotic protein expressions (e.g. Bcl-2 and Bcl-xL). GE also altered the expression of the autophagy-involved proteins. Furthermore, GE strongly reduced the expression of major antioxidant enzymes and increased the reactive oxygen species (ROS) generation in CRC cells, causing an imbalance of ROS metabolism. In conclusion, this study demonstrated that Gochujang exerts anticancer effects in CRC cells by inhibiting cell proliferation, increasing cell death, and interrupting ROS metabolism.

From parasitic life to health-promoting applications - A versatile goldmine discovered in nature's secret treasure chest: Orobanche nana

Studies evaluating the phytoconstituents and therapeutic potential of species belonging to Orobanche (Family Orobanchaceae) are rather limited. The present study was designed to evaluate the chemical composition, antioxidant, enzyme inhibition and cytotoxic properties of the aerial parts of Orobanche nana Noë ex Rchb. Extracts were prepared by sequential maceration in dichloromethane, ethyl acetate and ethanol and finally an aqueous extraction by infusion were performed. NMR and LC-DAD-MS analysis allowed the identification of different phytoconstituents including the characteristic compounds of Orobanche like verbascoside, poliumoside, orobanone and orobanchoside. The ethanol extract displayed the highest total phenolic (115.63 mg GAE/g) and flavonoids (16.53 mg RE/g) contents, antiradical (DPPH = 623.70 mg TE/g; ATBS = 843.50 mg TE/g) and ions reducing (Cu++ = 725.39; Fe+++ = 617.70) properties while the aqueous extract exerted the best chelating power (19.54 mg EDTAE/g). It was determined that EtOH and Water extracts applied to HepG2 cells decreased the levels of anti-apoptotic proteins p-NFκB, BCL-2 and BCL-XL, while increasing the levels of apoptotic proteins BAX and p-53, thus inhibiting cell survival. In addition, Orobanche nana played an active role in the rearrangement of overexpress MMPs that cause disruption of ECM homeostasis. We employed Network Pharmacology to investigate the mechanisms through which Orobanche nana's compounds impact Kidney and Liver diseases. These findings suggested that O. nana could be a promising source of bioactive molecules with potential therapeutic applications.

Therapeutic potential of monoterpene molecules acts against 7KCh-mediated oxidative stress and neuroinflammatory amyloidogenic signalling pathways

Alzheimer’s disease (AD) is a degenerative disorder characterised by amyloid-beta aggregates activated by the accumulation of lipid molecules and their derivatives, especially 7-ketocholesterol (7KCh), an oxidised lipid that plays a great part in the progression of AD. The current therapeutics need bio-potential molecules and their biomedical application preventing 7KCh-induced cytotoxicity. In this study, bornyl acetate (BA) and menthol (ME), the natural monoterpenes were investigated for their neuroprotective effects against 7KCh-induced SH-SY5Y cells and their effects were compared to the standard drug galantamine (GA). 7KCh-induced changes like lipid accumulation, amyloid generation, free radical generation, acetylcholinesterase levels, calcium accumulation and mitochondrial membrane integrity were analysed in SH-SY5Y cells with or without BA and ME treatment. Furthermore, various mediators involved in the amyloidogenic, inflammatory and apoptotic pathways were studied. In our results, the cells induced with 7KCh upon co-treatment with BA and ME significantly reduced lipid accumulation and amyloid generation through toll-like receptor (TLR) 4 suppression and enhanced ATP binding cassette (ABCA) 1-mediated clearance. Co-treatment with BA and ME concurrently regulated oxidative stress, acetylcholinesterase activity, mitochondrial membrane potential and intracellular calcification altered by 7KCh-induced SH-SY5Y cells. Moreover, 7KCh-induced cells showed elevated mRNA levels of misfolded protein markers and apoptotic mediators which were significantly downregulated by BA and ME co-treatment. In addition, the protein expression of amyloidogenic, proinflammatory as well as pro-apoptotic markers was decreased by BA and ME co-treatment in 7KCh-induced cells. Overall, BA and ME mediated inhibition of amyloidogenic activation and cell survival against 7KCh-induced inflammation, thereby preventing the onset and progression of AD in comparison to GA.

GenoMine: a CRISPR-Cas9-based kill switch for biocontainment of Pseudomonas putida.

Synthetic genetic circuits have revolutionised our capacity to control cell viability by conferring microorganisms with programmable functionalities to limit survival to specific environmental conditions. Here, we present the GenoMine safeguard, a CRISPR-Cas9-based kill switch for the biotechnological workhorse Pseudomonas putida that employs repetitive genomic elements as cleavage targets to unleash a highly genotoxic response. To regulate the system's activation, we tested various circuit-based mechanisms including the digitalised version of an inducible expression system that operates at the transcriptional level and different options of post-transcriptional riboregulators. All of them were applied not only to directly control Cas9 and its lethal effects, but also to modulate the expression of two of its inhibitors: the AcrIIA4 anti-CRISPR protein and the transcriptional repressor TetR. Either upon direct induction of the endonuclease or under non-induced conditions of its inhibitors, the presence of Cas9 suppressed cell survival which could be exploited beyond biocontainment in situations where further CRISPR genome editing is undesirable.

Anti-Skin Aging and Cytotoxic Effects of Methanol-Extracted Solanum betaceum Red Fruit Seed Extract on Ca9-22 Gingival Carcinoma Cells.

The tamarillo, or Solanum betaceum, recognized for its comprehensive nutritional profile, has long been valued for its diverse ethnobotanical uses. This study delves into the potential therapeutic applications of S. betaceum by analyzing its polyphenolic content (TPC), total flavonoid content (TFC), anti-skin aging activities against key enzymes like elastase, tyrosinase, and hyaluronidase, and its cytotoxic effects on oral carcinoma cells. Extracts from the seeds, pulp, and peel of red and yellow fruits were prepared using methanol, ethanol, and acetone. The highest TPC was found in the methanol extract from red fruit seeds (9.89 mg GAE/g), and the highest TFC was found in the methanol extract of yellow fruit peel (3.02 mg QUE/g). Some of these extracts significantly inhibited skin aging-associated enzymes with the red fruit seed extract (100 μg/mL) showing up to 50.4% inhibition of tyrosinase. Additionally, the red fruit seed extract obtained using methanol demonstrated potential anticancer effects against Ca9-22 oral carcinoma cells by inhibiting cell survival, migration, and proliferation as well as inducing apoptosis. These results underscore the potential of S. betaceum fruit extracts, especially from red fruit seeds, as promising agents for anti-skin aging and anticancer applications, meriting further exploration for therapeutic uses.

Anti-Skin Aging Potential, Antibacterial Activity, Inhibition of Single-Stranded DNA-Binding Protein, and Cytotoxic Effects of Acetone-Extracted Passiflora edulis (Tainung No. 1) Rind Extract on Oral Carcinoma Cells.

The passion fruit, Passiflora edulis, recognized for its rich nutritional properties, has long been used for its varied ethnobotanical applications. This study investigates the therapeutic potential of P. edulis var. Tainung No. 1 rind extracts by examining their polyphenolic content (TPC), total flavonoid content (TFC), anti-skin aging activities against key enzymes such as elastase, tyrosinase, and hyaluronidase, and their ability to inhibit bacterial growth, single-stranded DNA-binding protein (SSB), and their cytotoxic effects on oral carcinoma cells. The acetone extract from the rind exhibited the highest levels of TPC, TFC, anti-SSB, and antibacterial activities. The antibacterial effectiveness of the acetone-extracted rind was ranked as follows: Escherichia coli > Pseudomonas aeruginosa > Staphylococcus aureus. A titration curve for SSB inhibition showed an IC50 value of 313.2 μg/mL, indicating the potency of the acetone extract in inhibiting SSB. It also significantly reduced the activity of enzymes associated with skin aging, particularly tyrosinase, with a 54.5% inhibition at a concentration of 100 μg/mL. Gas chromatography-mass spectrometry (GC-MS) analysis tentatively identified several major bioactive compounds in the acetone extract, including stigmast-5-en-3-ol, vitamin E, palmitic acid, stigmasterol, linoleic acid, campesterol, and octadecanoic acid. Molecular docking studies suggested some of these compounds as potential inhibitors of tyrosinase and SSB. Furthermore, the extract demonstrated anticancer potential against Ca9-22 oral carcinoma cells by inhibiting cell survival, migration, and proliferation and inducing apoptosis. These results underscore the potential of P. edulis (Tainung No. 1) rind as a promising candidate for anti-skin aging, antibacterial, and anticancer applications, meriting further therapeutic investigation.

Morin overcomes doxorubicin resistance in human breast cancer by inducing DNA damage and modulating the LKB1/AMPK/mTORC1 signaling pathway.

Breast cancer chemoresistance hampers chemotherapy efficacy; researchers investigate the pharmacological activities of natural products for potential solutions. This study aimed to determine the effect of morin, a bioflavonoid isolated from Maclura pomifera, on two Dox-resistant human breast cancer cell lines MDA-MB-231 (MDA-DR) and MCF-7 (MCF-DR). Sulforhodamine B and colony-forming assays demonstrated the cytotoxic effect of morin on both cell lines. Morin induced DNA damage and reduced the DNA repair mechanism, a feature of chemoresistance. In addition, morin reduced the protein expressions of cell cycle regulators, such as cyclin D1, CDK4, cyclin E1, cyclin B1, and p-Rb, thereby halting cell cycle progression. Moreover, morin slightly reduced PARP and Bcl-xL expressions but left LC3-II and RIPK3 expressions unchanged. Annexin-V/7-AAD analysis showed morin increased 7-AAD positive cells and annexin-V positive cells among MDA-DR and MCF-DR cells, respectively. In addition, morin increased p-AMPK and p-LKB1 levels; and, thus, inhibited phosphorylation of the mTOR pathway, but decreased t-AMPK levels by inducing lysosomal degradation, and AICAR, an AMPK activator, reduced Raptor, cyclin D1, CDK4, cyclin E1 and phosphorylated, and total mTOR levels, indicating AMPK is a key player in inducing cell death. Also, morin modulated MAPK phosphorylation and attenuated p-Akt and p-GSK3αβ levels; and thus, inhibited cell survival. In addition, morin suppressed tumor growth in our MDA-DR xenografted mouse model. These findings indicate that morin is a potential treatment for Dox-resistant breast cancer and that it does so by inducing DNA damage and modulating the LKB1/AMPK/mTORC1 pathway, along with regulating the MAPK, and Akt/GSK3αβ signaling pathways.

Biological Activity of Natural and Synthetic Peptides as Anticancer Agents.

Cancer is one of the leading causes of morbidity and death worldwide, making it a serious global health concern. Chemotherapy, radiotherapy, and surgical treatment are the most used conventional therapeutic approaches, although they show several side effects that limit their effectiveness. For these reasons, the discovery of new effective alternative therapies still represents an enormous challenge for the treatment of tumour diseases. Recently, anticancer peptides (ACPs) have gained attention for cancer diagnosis and treatment. ACPs are small bioactive molecules which selectively induce cancer cell death through a variety of mechanisms such as apoptosis, membrane disruption, DNA damage, immunomodulation, as well as inhibition of angiogenesis, cell survival, and proliferation pathways. ACPs can also be employed for the targeted delivery of drugs into cancer cells. With over 1000 clinical trials using ACPs, their potential for application in cancer therapy seems promising. Peptides can also be utilized in conjunction with imaging agents and molecular imaging methods, such as MRI, PET, CT, and NIR, improving the detection and the classification of cancer, and monitoring the treatment response. In this review we will provide an overview of the biological activity of some natural and synthetic peptides for the treatment of the most common and malignant tumours affecting people around the world.

ARID1A is involved in DNA double-strand break repair in gastric cancer.

Defects in DNA damage repair can cause genetic mutations, which in turn can cause different types of cancers. Chromatin remodeling complexes, which help repair damaged DNA, can cause the chromatin structure to change as a result of DNA damage. ARID1A may play a role in the process of DNA damage repair, and arid1a may be related to the occurrence and development of gastric cancer (GC). This study aimed to investigate the mechanism of ARID1A regulating the DNA damage repair of gastric adenocarcinoma cell lines AGS and SGC-7901 and its effect on migration, proliferation and apoptosis. The expression of ARID1A plasmid was detected by Western blot and real-time polymerase chain reaction (PCR). The effect of etoposide (ETO) on the survival rate of AGS and SGC-7901 gastric adenocarcinoma cell lines was detected by MTT assay. The DNA double-strand break model was established by ETO and then passed through the comet assay and immunofluorescence co-localization to observe DNA damage; western blot method was used to detect the effect of ARID1A on the expression of related proteins in DNA damage repair pathway in gastric adenocarcinoma cells; scratch test and colony formation experiments were used to observe ARID1A migration and proliferation of gastric adenocarcinoma cells. The flow cytometry was used to detect the effect of ARID1A on apoptosis of gastric adenocarcinoma cells. The expression of mRNA and protein was increased after transfection of ARID1A plasmid. ETO was confirmed by MTT assay to inhibit cell survival in a dose-dependent manner. After the DNA double-strand break model was established by ETO, the expression levels of phospho-ataxia telangiectasia mutated (p-ATM) protein increased in the overexpressed ARID1A group. Meanwhile, the overexpressed ARID1A group had a shortened tail moment, and γ-H2AX and ARID1A co-localized in the DNA damage site of the nucleus. The over-expressed ARID1A group had weaker wound healing ability, reduced number of clone formation, and increased apoptosis rate. ARID1A may repair DNA double-strand breaks caused by ETO by p-ATM pathway; ARID1A can inhibit the migration and proliferation of gastric adenocarcinoma cells and promote apoptosis. Our findings indicate that ARID1A could serve as a therapeutic target and biomarker for GC patients.

Metformin-induced oxidative stress inhibits LNCaP prostate cancer cell survival.

Preclinical and clinical studies over the past several decades have indicated the potential value of metformin, a widely utilized treatment for Type 2 diabetes, in prostate cancer therapy. Notably, these studies demonstrated metformin's pleiotropic effects on several molecular and metabolic pathways, such as androgen signaling, cell cycle, and cellular bioenergetics. In this study we investigated the role of metformin in regulating intracellular redox status and cell survival in LNCaP prostate cancer cells. The cytotoxic effects of metformin with or without the presence of SBI0206965 (AMPK inhibitor) on LNCaP cells were determined using MTT and trypan blue exclusion assays. Seahorse XP extracellular analysis, Liquid Chromatography/ Mass Spectrophotometry (LC/MS), and 2,7- and Dichlorofluoresin diacetate (DCFDA) assay were used to assess the effects of metformin on cellular bioenergetics, redox status, and redox-related metabolites. mRNA expression and protein concentration of redox-related enzymes were measured using Real Time-qPCR and ELISA assay, respectively. Independently of AMP-activated protein kinase, metformin exhibited a dose- and time-dependent inhibition of LNCaP cell survival, a response mitigated by glutathione or N-acetylcysteine (ROS scavengers) treatment. Notably, these findings were concomitant with a decline in ATP levels and the inhibition of oxidative phosphorylation. The results further indicated metformin's induction of reactive oxygen species, which significantly decreased glutathione levels and the ratio of reduced to oxidized glutathione, as well as the transsulfuration metabolite, cystathionine. Consistent with an induction of oxidative stress condition, metformin increased mRNA levels of the master redox transcription factor Nrf-2 (nuclear factor erythroid-derived 2-like), as well as transsulfuration enzymes cystathionine beta-synthase and cystathionase and GSH synthesis enzymes γ-glutamylcysteine synthetase and glutathione synthetase. Our findings highlight multiple mechanisms by which metformin-induced formation of reactive oxygen species may contribute to its efficacy in prostate cancer treatment, including promotion of oxidative stress, Nrf2 activation, and modulation of redox-related pathways, leading to its anti-survival action.

Integrated Transcriptome Analysis of Radioresistant Cells Revealed Genes and Pathways Predictive Of Tumor Response to Radiotherapy and Chemotherapy in Breast Cancer

AbstractBreast cancer cells exposed to radiotherapy frequently develop radiation resistance through molecular and phenotypic changes. While there is evidences of pathways controlling radioresistance, the evolution of diverse cell phenotypes and transcriptional changes as mediators of radioresistance in breast cancer are restricted. Moreover, the effectiveness of the chemotherapy on radioresistant cells remains uncertain. In this work, an isogenic model of radioresistant breast cancer cells (RR cells) is used to study this phenotype. RR cells show high survival rates after radiation, moreover, RR cells of the triple negative breast cancer (TNBC) subtype show a significantly advanced invasiveness phenotype. Notably, RR cells are significantly sensitive to chemotherapy by inhibit cell survival and promote apoptosis. Transcriptomics and gene co‐expression network analysis identify differentially expressed genes (DEGs) and hub genes related to survival and apoptosis pathways in the RR cells of luminal subtype, while in TNBC subtype, cell migration, cell differentiation, and immune pathways are enriched. Hub genes predict the failure of radiotherapy in breast cancer patients, but they are also related to pathological complete response after chemotherapy. Transcriptome changes during acquired radioresistance uncover genes and pathways associated to radio and chemotherapy response. These results demonstrate that radioresistant pathways may converge to develop collateral chemo‐sensitivity.