The E3 ubiquitin ligase TRIM17 promotes gastric cancer survival and progression via controlling BAX stability and antagonizing apoptosis

Cell Death and Differentiation, Journal Year: 2023, Volume and Issue: 30(10), P. 2322 - 2335

Published: Sept. 11, 2023

Language: Английский

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Anti‐apoptotic protein BCL‐XL as a therapeutic vulnerability in gastric cancer

Animal Models and Experimental Medicine, Journal Year: 2023, Volume and Issue: 6(3), P. 245 - 254

Published: June 1, 2023

New therapeutic targets are needed to improve the outcomes for gastric cancer (GC) patients with advanced disease. Evasion of programmed cell death (apoptosis) is a hallmark cells and direct induction apoptosis by targeting pro-survival BCL2 family proteins represents promising strategy treatment. Therefore, understanding molecular mechanisms underpinning survival could provide basis potential interventions.Here we explored role BCL2L1 encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR (ddPCR) technology investigate DNA amplification GC samples lines, sensitivity lines selective inhibitors A1155463 A1331852, pan-inhibitor ABT-263, VHL-based PROTAC-BCL-XL was analyzed using (CellTiter-Glo) CTG assay vitro. Western Blot (WB) used detect protein expression members manner which kills cells. Co-immunoprecipitation (Co-IP) mechanism A1331852 ABT-263 lines. DDPCR, WB, real-time (RTPCR) were correlation between DNA, RNA, levels, drug activity.The functional showed that subset relies on survival. In more sensitive than pan inhibitor indicating not an optimal BCL-XL. DT2216 appears be active induces time- dose-dependent through proteasome pathway. Statistical analysis level predicts response therapy gene CNVs do reliably predict expression.We identified as target cases high levels expression. Functionally, demonstrated both PROTAC can potently kill reliant However, found copy number variations (CNVs) cannot expression, but serves useful biomarker predicting BCL-XL-targeting compounds. Taken together, our study pinpointed druggable specific subsets

Language: Английский

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The Interplay between Medical Plants and Gut Microbiota in Cancer

Nutrients, Journal Year: 2023, Volume and Issue: 15(15), P. 3327 - 3327

Published: July 26, 2023

The gut microbiota is a dynamic community of bacteria distributed in the gastroenteric tract and changes response to diseases, diet, use antibiotics probiotics, hygiene status, other environmental factors. Dysbiosis, disruption normal crosstalk between host microbes, associated with obesity, diabetes, cancer, cardiovascular linked reduction anti-inflammatory like Lactobacillus Roseburia, an increase growth proinflammatory species Ruminococcus gnavus Bacteroidetes. Some plants possess anticancer properties various studies have reported that some these are also able modulate microbiota. aim this work evaluate crucial relationship medical consequences on onset progression cancer. In vivo about hematological malignancies showed beta-glucans tie endogenous antibeta glucan antibodies iC3b, opsonic fragment central complement protein C3, leading phagocytosis antibody-targeted neoplastic cells potentiation cytotoxic activity innate immune system if administered together monoclonal antibodies. conclusion, review suggests potential improve dysbiosis assist treatment

Language: Английский

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First-in-Human Study with Preclinical Data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 30(3), P. 506 - 521

Published: Nov. 16, 2023

Abstract Purpose: B-cell lymphoma-extra-large (BCL-xL) regulates apoptosis and is an attractive anticancer therapeutic target. However, BCL-xL inhibition also kills mature platelets, hampering clinical development. Using innovative prodrug strategy, we have developed pelcitoclax (APG-1252), a potent, dual BCL-2 inhibitor. Aims of this study were to characterize the antitumor activity safety explore its underlying mechanisms action (MOA). Patients Methods: Cell line–derived xenograft patient-derived (PDX) models tested evaluate elucidate MOA. Subjects (N = 50) with metastatic small-cell lung cancer other solid tumors received intravenous once or twice weekly. Primary outcome measures tolerability; preliminary efficacy (responses every 2 cycles per RECIST version 1.1) represented secondary endpoint. Results: Pelcitoclax exhibited strong BAX/BAK‒dependent caspase-mediated antiproliferative apoptogenic in various cell lines. Consistent cell-based activity, disrupted BCL-xL:BIM BCL-xL:PUMA complexes gastric PDX models. Levels correlated tumor growth by pelcitoclax. Combined taxanes, enhanced downregulating antiapoptotic protein myeloid leukemia-1 (MCL-1). Importantly, was well tolerated demonstrated efficacy, overall response disease control rates 6.5% 30.4%, respectively. Most common treatment-related adverse events included transaminase elevations reduced platelets that less frequent once-weekly schedule. Conclusions: Our data demonstrate has tolerated, supporting further development for human tumors, particularly combined agents downregulate MCL-1.

Language: Английский

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Eternal Youth: A Comprehensive Exploration of Gene, Cellular, and Pharmacological Anti-Aging Strategies

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(1), P. 643 - 643

Published: Jan. 4, 2024

The improvement of human living conditions has led to an increase in average life expectancy, creating a new social and medical problem—aging, which diminishes the overall quality life. aging process body begins with activation effector signaling pathways cells, resulting loss their normal functions deleterious effects on microenvironment. This, turn, leads chronic inflammation similar transformations neighboring cells. cumulative retention these senescent cells over prolonged period results deterioration tissues organs, ultimately leading reduced elevated risk mortality. Among most promising methods for addressing age-related illnesses are pharmacological, genetic, cellular therapies. Elevating activity aging-suppressing genes, employing specific groups native genetically modified utilizing senolytic medications may offer potential delay ailments long term. This review explores strategies advancements field anti-aging therapies currently under investigation, particular emphasis gene therapy involving adeno-associated vectors cell-based therapeutic approaches.

Language: Английский

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DETERMINATION OF THE ANTIPROLIFERATIVE EFFECT OF STERNBERGIA LUTEA (L.) KER GAWL. EX SPRENG. EXTRACTS ON A375 MALIGNANT MELONOMA CELL LINE

Eskişehir Teknik Üniversitesi Bilim ve Teknoloji Dergisi - C Yaşam Bilimleri Ve Biyoteknoloji, Journal Year: 2025, Volume and Issue: 14(1), P. 25 - 33

Published: Jan. 29, 2025

Epidemiological evidence confirms that plants are primary sources of drugs used to reduce the incidence cancer and prevent cancer-related deaths. Sternbergia species for therapeutic purposes due amaryllidaceae alkaloids, lectins, phenolic acids, pigments, volatile components they contain. In this study, anticancer properties S. lutea extracts were tested on A375 malignant melonoma cell line. addition, in transcriptional expression BCL-XL Cas9 genes, which function proliferation apoptotic pathways, cells treated with plant determined by qRT-PCR. According cytotoxicity results made MTT test, highest inhibition percentage was at plant's concentration 500 μg/𝑚L. At concentration, inhibited 83.63%, IC50 value extract calculated as 194.64 qRT-PCR analyses, a statistically significant increase observed mRNA levels positively correlated pathway, cisplatin-applied groups compared control group.

Language: Английский

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Both direct and indirect suppression of MCL1 synergizes with BCLXL inhibition in preclinical models of gastric cancer

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 12, 2025

Abstract Despite the progress of treatment in gastric cancer (GC), overall outcomes remain poor patients with advanced diseases, underscoring urgency to develop more effective strategies. BH3-mimetic drugs, which inhibit pro-survival BCL2 family proteins, have demonstrated great therapeutic potential therapy. Although previous studies implicated a role targeting cell survival pathway GC, contribution different proteins promoting and mediating resistance current standard therapies GC remains unclear. A systematic study elucidate hierarchy these using clinically relevant models is essential identify most target(s) rational combination strategies for improving Here, we provide evidence from both vitro vivo broad panel lines, tumoroids, xenograft demonstrate that BCLXL MCL1, but not other are crucial cells survival. While small molecular inhibitors or MCL1 exhibited some single-agent activity, their sufficed cause maximum killing. However, due unsolved cardiotoxicity associated direct inhibitors, finding combinations agents indirectly target enable reduction doses while maintaining anti-neoplastic effects potentially feasible approach further development compounds. Importantly, inhibiting synergized significantly anti-mitotic HER2-targeting leading enhanced anti-tumour activity tolerable toxicity preclinical models. Mechanistically, chemotherapies induced degradation via ubiquitin-proteasome mainly through FBXW7, whereas drugs suppressed transcription STAT3/SRF axis. Moreover, co-targeting STAT3 also synergistic killing, extending beyond HER2-amplified GC. Collectively, our results mechanistic rationale pre-clinical (both directly indirectly)

Language: Английский

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Cellular and Molecular Mechanisms of Chemoresistance for Gastric Cancer

International Journal of General Medicine, Journal Year: 2024, Volume and Issue: Volume 17, P. 3779 - 3788

Published: Aug. 1, 2024

Gastric cancer (GC) is one of the most common malignant tumors in digestive tract, and chemotherapy plays an irreplaceable role comprehensive treatment GC. However, chemoresistance makes it difficult for patients with GC to benefit steadily from long term, which ultimately leads tumor recurrence, metastasis, patient death. Elucidating detailed mechanism identifying specific therapeutic targets will help solve problem improve prognosis This review summarizes clarifies cellular molecular mechanisms underlying

Language: Английский

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Possibilities of gene, cellular and pharmacological approaches to correct age-related changes

Kazan medical journal, Journal Year: 2024, Volume and Issue: 105(6), P. 974 - 986

Published: Nov. 7, 2024

Improvement of the human habitat has led to an increase in average life expectancy. Long goes hand with old age, which reduces quality and it is acute social problem. Thus, search for approaches that can improve life, ability live without age-related diseases extremely urgent task. Aging body begins aging cells, activation process occurs through induction specific signaling pathways, irreversibly divides any cell into “before after”. cells are able influence their microenvironment, secreting more inflammatory molecules inducing pathological changes neighboring cells. The accumulation long-term preservation aged lead deterioration condition tissues organs, ultimately a decrease increased risk death. Among most promising correction pharmacological, gene therapy. Increasing expression suppressor genes, using certain populations native genetically modified as well senolytic drugs help delay associated distant future. This review examines currently studied achievements field anti-aging therapy, particular therapy adeno-associated vectors based on

Language: Английский

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Eternal Youth: A Comprehensive Exploration of Gene, Cellular, and Pharmacological Anti-aging Strategies

Published: Dec. 25, 2023

The enhancement of human living conditions has resulted in an increase average life expectancy, giving rise to a novel social and medical challenge: aging, which diminishes the overall quality life. aging process body begins through activation effector signaling pathways cells, loss their normal functions deleterious effects on microenvironment, leads chronic inflammation similar transformation neighboring cells. cumulative retention these senescent cells over prolonged period results deterioration tissues organs, ultimately leading reduced elevated mortality risk. Among most encouraging methods for addressing age-related illnesses are pharmacological, genetic, cellular therapies. Elevating activity aging-suppressing genes, employing specific groups native genetically modified utilizing senolytic medications may offer potential delay ailments long term. review explores strategies advancements field anti-aging therapies that currently under investigation, with particular emphasis gene therapy involving adeno-associated vectors cell-based therapeutic approaches.

Language: Английский

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