Overcome Chemotherapy Resistance Research Articles

Lactylation in cancer: Mechanisms in tumour biology and therapeutic potentials.

Lactylation, a recently identified form of protein post-translational modification (PTM), has emerged as a key player in cancer biology. The Warburg effect, a hallmark of tumour metabolism, underscores the significance of lactylation in cancer progression. By regulating gene transcription and protein function, lactylation facilitates metabolic reprogramming, enabling tumours to adapt to nutrient limitations and sustain rapid growth. Over the past decade, extensive research has revealed the intricate regulatory network underlying lactylation in tumours. Large-scale sequencing and machine learning have confirmed the widespread occurrence of lactylation sites across the tumour proteome. Targeting lactylation enzymes or metabolic pathways has demonstrated promising anti-tumour effects, highlighting the therapeutic potential of this modification. This review comprehensively explores the mechanisms of lactylation in cancer cells and the tumour microenvironment. We expound on the application of advanced omics technologies for target identification and data modelling within the lactylation field. Additionally, we summarise existing anti-lactylation drugs and discuss their clinical implications. By providing a comprehensive overview of recent advancements, this review aims to stimulate innovative research and accelerate the translation of lactylation-based therapies into clinical practice. KEY POINTS: Lactylation significantly influences tumour metabolism and gene regulation, contributing to cancer progression. Advanced sequencing and machine learning reveal widespread lactylation sites in tumours. Targeting lactylation enzymes shows promise in enhancing anti-tumour drug efficacy and overcoming chemotherapy resistance. This review outlines the clinical implications and future research directions of lactylation in oncology.

Morphological assessment of angiogenesis factor expression in tumor and microenvironment of breast fibroadenoma and ductal carcinoma: An observational cohort study

Background. Angiogenesis plays a crucial role in the progression of breast cancer. Identifying and investigating the key components of this process, focused on phenotype as well as microenvironment of the tumor, is considered highly relevant for understanding tumor biology. Studies into the expression of angiogenesis-related factors by means of immunohistochemical methods appear valuable for both assessing conventional chemotherapy options and identifying new targets in targeted therapy for breast cancer. Objectives. To investigate angiogenesis in breast ductal carcinoma by assessing the expression of vascular endothelial growth factor, angiopoietin-2, and hypoxia-inducible factor alpha in the context of various therapeutic strategies. Methods. An observational cohort study was conducted using biopsy samples from female patients with confirmed diagnoses of “fibroadenoma” and “ductal carcinoma of the breast,” residents of the Republic of Crimea, who applied to oncological hospitals in Simferopol from January 2021 to January 2023. Examination involved histological sections of breast tumor tissue from 68 patients with verified diagnoses of “ductal carcinoma” and “fibroadenoma” (the mean age of the patients was 65 ± 5). The following cohorts were formed in the study: control group, consisting of patients with breast fibroadenoma (n = 20); two subgroups of patients with ductal carcinoma of the breast (n = 48), including Group I — patients with ductal carcinoma of the breast who had not received chemotherapy (n = 23), Group II — patients with ductal carcinoma of the breast, who underwent surgery following one or more courses of chemotherapy (n = 25). The study involved examining the tumor tissue sections obtained from paraffin blocks, assessing the expression of angiogenesis markers via immunohistochemistry using primary antibodies against vascular endothelial growth factor, angiopoietin 2, and hypoxia-inducible factor alpha. Statistical analysis was carried out using Statistica 10.0 (StatSoft, USA). Differences were considered significant at error probability p ≤ 0.05. The value of p < 0.05 was deemed statistically significant for all types of analysis. Results. The expression of hypoxia-inducible and vascular growth factors differed significantly between both groups with breast ductal carcinoma as well as when compared to the control group. The hypoxia-inducible factor having cytoplasmic localization was detected in the control group with benign processes, whereas the nuclear expression was noted in the breast ductal carcinoma groups. Significant differences in the nuclear expression of hypoxia-inducible factor have been established among groups of patients with confirmed ductal carcinoma of the breast: in Group II, which underwent chemotherapy, expression was notably higher in both the tumor stroma and in the stroma of tumor-free areas. The hypoxia-inducible factor expression was significantly greater at the demarcation zone than that observed in samples from surgically treated women in Group I (p = 0.033; p = 0.034, p < 0.001, respectively). In the tumor epithelium of patients with breast ductal carcinoma, vascular endothelial growth factor was expressed significantly more intensively in the group who did not receive chemotherapy compared to the other group (p < 0.001). Conversely, in the tumor stroma, angiopoietin exhibited significantly higher expression levels among patients who underwent chemotherapy compared to those who received no treatment; this was observed in both the tumor areas due to endothelial cell involvement (p = 0.004) and in conditionally healthy regions of the breast (p < 0.001). In the control group represented by fibroadenoma patients, the expression of the studied factors is more pronounced than in the groups with ductal carcinoma of the breast. Conclusion. The obtained data indicate the activation of angiogenesis processes in the group of patients after chemotherapy, as evidenced by the increased expression of hypoxia-inducible factor, vascular endothelial growth factor, and angiopoietin. This result is associated with the high prevalence of resistant forms of breast ductal carcinoma in Group II. The study of the signaling pathways of angiogenesis and its components provides valuable insights into patterns of occurrence and strategies to overcome chemotherapy resistance in ductal carcinoma of the breast.

SiRNA-based strategies to combat drug resistance in gastric cancer.

Chemotherapy is a key treatment option for gastric cancer, but over 50% of patients develop either inherent or acquired resistance to these drugs, resulting in a 5-year survival rate of only about 20%. The primary treatment for advanced gastric cancer typically involves chemotherapy based on platinum or fluorouracil. Several factors can contribute to platinum resistance, including decreased drug uptake, increased drug efflux or metabolism, enhanced DNA repair, activation of pro-survival pathways, and inhibition of pro-apoptotic pathways. In recent years, there has been significant progress in biology aimed at finding innovative and more effective methods to overcome chemotherapy resistance. Small interfering RNAs (siRNAs) have emerged as a significant advancement in gene expression regulation, showing promise in enhancing the sensitivity of gastric cancer cells to chemotherapy drugs. However, siRNA therapies still face major challenges, particularly in terms of stability and efficient delivery in vivo. This article discusses the advances in siRNA therapy and its potential role in overcoming resistance to chemotherapeutic drugs such as cisplatin, 5-FU, doxorubicin, and paclitaxel in the treatment of gastric cancer.

In vivo delivery of PBAE/ZIF-8 enhances the sensitivity of colorectal cancer to doxorubicin through sh-LncRNA ASB16-AS1.

The aim of this study is to investigate the impact of sh-LncRNA ASB16-AS1 on doxorubicin (DOX) resistance in colorectal cancer (CRC). First, an in vitro study was conducted to investigate the effects of LncRNA ASB16-AS1, miR-185-5p, and TEAD1 on drug resistance in CRC cells. Subsequently, utilizing nanotechnology, poly(beta amino esters) (PBAE)/zeolitic imidazolate framework-8 (ZIF-8)@sh-LncRNA ASB16-AS1 nanoparticles (PZSNP) were synthesized and characterized, evaluating their cellular toxicity and hemolytic activity. Finally, a mouse subcutaneous tumor model was established by subcutaneous injection of SW480/DOX cell suspension to investigate the impact of PZSNP on the tumor. Under DOX treatment, downregulation of LncRNA ASB16-AS1, overexpression of miR-185-5p, or downregulation of TEAD1 suppressed the viability and proliferation of drug-resistant CRC cells while promoting apoptosis. Conversely, overexpression of LncRNA ASB16-AS1, inhibition of miR-185-5p, or overexpression of TEAD1 enhanced the viability and proliferation of drug-resistant CRC cells while inhibiting apoptosis. The synthesized PZSNP exhibited a spherical shape with an average particle size of 123.6 nm, possessed positive charge, displayed good stability. It effectively encapsulated shRNA and displayed low cellular toxicity and hemolytic activity. Under DOX treatment, significant tumor necrosis was observed in the PZSNP group, and tumor growth was suppressed without causing weight loss. LncRNA ASB16-AS1, miR-185-5p, and TEAD1 are involved in regulating cell viability, proliferation, and apoptosis, contributing to drug resistance in CRC cells. sh-LncRNA ASB16-AS1 enhances the sensitivity of CRC cells to DOX during treatment, and in vivo delivery of PZSNP may serve as an effective strategy to overcome chemotherapy resistance in CRC.

Matrine alkaloids modulating DNA damage repair in chemoresistant non-small cell lung cancer cells

BackgroundNon-small cell lung cancer (NSCLC) presents a significant challenge in the medical field due to its high incidence and resistance to chemotherapy. Chemoresistance in NSCLC diminishes treatment efficacy and contributes to poor patient outcomes. Matrine alkaloids have shown promise in reversing chemotherapy resistance in NSCLC by targeting DNA repair mechanisms.MethodsUtilizing molecular dynamics simulations, we explored the interactions between Matrine alkaloids and DNA repair-related proteins to elucidate their impact on NSCLC cells. In vitro experiments involved treating A549/DDP cells with Matrine alkaloids to evaluate their sensitizing effects on lung cancer cells. Additionally, animal model experiments were conducted to validate the therapeutic potential of Matrine alkaloids in NSCLC treatment.ResultsOur findings demonstrate that Matrine alkaloids disrupt DNA damage repair processes in NSCLC cells, leading to increased sensitivity to chemotherapy. Molecular docking studies revealed the intricate mechanisms by which Matrine alkaloids interact with DNA repair proteins, impacting cell survival and proliferation. Both cell experiments and animal models confirmed the chemosensitizing effects of Matrine alkaloids in NSCLC treatment.ConclusionMatrine alkaloids offer a promising avenue for overcoming chemotherapy resistance in NSCLC by interfering with DNA repair pathways. This study lays a solid foundation for future clinical investigations into the potential of Matrine alkaloids as effective therapeutic agents for enhancing NSCLC treatment outcomes.

Cultures derived from pancreatic cancer xenografts with long-term gemcitabine treatment produce chemoresistant secondary xenografts: Establishment of isogenic gemcitabine-sensitive and -resistant models

In attempts to establish sophisticated models to reproduce the process of acquired drug resistance, we transformed normal human pancreatic ductal epithelial cells by introducing genes for multiple cellular factors. We also created isogenic gemcitabine-sensitive and -resistant models by short- and long-term gemcitabine treatment, respectively. These models demonstrated differences in drug resistance in vivo, but not in vitro. Gemcitabine treatment also induced squamous transdifferentiation in xenografts in mice. The transcription factor p63 was identified as a possible resistance-determining factor but was unlikely to be solely responsible for the resistance to gemcitabine. This system would prove useful to discover novel molecular targets to overcome chemotherapy resistance, by allowing the evaluation of molecules of interest in xenograft models after in vitro genetic ablation.

LAMTOR1 ablation impedes cGAS degradation caused by chemotherapy and promotes antitumor immunity

Chemotherapy resistance remains a significant obstacle that limits the long-term efficacy of cancer therapy, necessitating further investigations into the underlying mechanisms. Here, we find that DNA fragments induced by chemotherapeutic agents trigger the degradation of cGAS, a potent double-strand DNA (dsDNA) sensor, by lysosomes. Mechanically, the lysosome-localized protein LAMTOR1 is up-regulated, and the interaction between LAMTOR1 and cGAS is enhanced upon exposure to DNA fragments, boosting the accumulation and digestion of cGAS in lysosomes through the receptor protein p62. LAMTOR1 deficiency increases cGAS abundance and promotes activation of the cGAS-STING pathway, leading to subsequent production of type I interferons induced by cytosolic DNA stimulation. Loss of LAMTOR1 synergizes with immunotherapy and chemotherapy to inhibit tumor growth and prolong the survival time of tumor-bearing mice by promoting the infiltration of effective T lymphocytes. Thus, our study reveals a regulation of cGAS abundance and provides a potential strategy to overcome chemotherapy resistance by targeting LAMTOR1.

Cepharanthine sensitizes gastric cancer cells to chemotherapy by targeting TRIB3-FOXO3-FOXM1 axis to inhibit autophagy

BackgroundGastric cancer is among the common solid tumors. Chemotherapy resistance is the most common issue in gastric cancer treatment. Inhibiting intracellular autophagy may be a feasible method for overcoming chemotherapy resistance. Cepharanthine (CEP), a natural small molecule extracted from the stephania cephalantha Hayata plant, has been demonstrated to significantly inhibit cancer growth and can regulate autophagy. Although CEP can significantly inhibit cancer growth, it remains unclear whether CEP can regulate autophagy in gastric cancer. This study aimed to investigate whether CEP can enhance the sensitivity of gastric cancer to chemotherapy and elucidate its molecular mechanism. MethodsThree gastric cancer cell lines (AGS, SGC7901, and MFC) and one normal gastric mucosal epithelial cell line (GES-1) were used for in vitro experiments. The characterization of autophagy in gastric cancer cells included the detection of autophagy markers and autophagy flux through immunofluorescence staining and Western blotting, as well as the assessment of lysosomal function using fluorescence staining (LysoTracker Red DND-99, Acridine Orange staining) and Western blotting. The cytotoxicity of CEP, autophagy inhibitors (chloroquine [CQ] and 3-methyladenine [3MA]), and chemotherapy drugs (doxorubicin [DOX] and cisplatin [CIS]) was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell colony formation, and fluorescence staining techniques (H2DCFDA, Dihydroethidium, and JC-1 staining). The interaction between CEP and autophagy inhibitors was tested in a 615 mice model, and changes in the gut microbiota were determined through accurate 16S absolute quantification sequencing. The signaling pathway and autophagy regulatory target TRIB3-FOXO3-FOXM1 were confirmed through molecular docking, RNA sequencing, bioinformatic analysis, transfection techniques, and Western blotting. ResultsCEP blocked autophagic flux in gastric cancer cells without affecting lysosomal function. As a novel autophagy inhibitor, CEP could combine with conventional autophagy inhibitors (CQ and 3MA) to block intracellular autophagy, thereby inhibiting gastric cancer growth. During this process, changes in the gut microbiota were observed, including low-level changes in Odoribacterium, Erysipelatoclostridium, and ParaPrevotella and high-level changes in Ileibacterium, Enterorhabdus, and Bifidobacterium. Additionally, CEP synergistically inhibited the growth of gastric cancer when combined with chemotherapy drugs. Mechanistically, the TRIB3-FOXO3-FOXM1 signaling axis was found to be involved in the inhibition of gastric cancer by CEP combined with autophagy inhibitors and chemotherapy drugs, thereby mediating cell apoptosis. ConclusionThis study links the TRIB3-FOXO3-FOXM1 axis with chemotherapy efficacy. Our findings demonstrated that CEP inhibits autophagy by modulating the FOXO3-FOXM1 axis. When combined with chemotherapy drugs (DOX and CIS), CEP, as an autophagy inhibitor, can limit TRIB3 protein expression, thereby regulating the FOXO3-FOXM1 axis and enhancing its ability to prevent gastric cancer growth. These findings may contribute to improving the prognosis of patients with gastric cancer. Furthermore, these results enrich the fundamental understanding of how autophagy inhibition can enhance clinical cancer treatment efficacy and provide insights into the potential mechanisms by which CEP functions as an anti-tumor drug, thereby exploring its value for clinical application.

Delivery of doxorubicin by Fe3O4 nanoparticles, reduces multidrug resistance gene expression in ovarian cancer cells

BackgroundOvarian cancer is one of the most common malignancy in women with significant mortality rate due to the resistance to chemotherapy drugs. Doxorubicin (DOX) is a chemotropic agent in ovarian cancer treatment. Overexpression of multidrug resistance (MDR) genes, such as ABCB1, in cancer cells after chemotherapy is one of main problems in clinical applications. Here we have compared the efficiency of doxorubicin-loaded (NIPAAM-DMAEMA) Fe3O4 nanocomposite (DOX-NANO) against DOX on ABCB1(MDR1) gene expression in the ovarian cancer cell line. Materials and MethodsThe cell viability of SKOV-3 cells were evaluated by MTT assay. Real Time PCR was used to measure the expression level of MDR1. MTT data were normalized in 10 different attribute weighting models, also to reveal the interaction between DOX, ABCB1, and ovarian cancer genes, Pathway Studio Database (Elsevier) was used. ResultsCell viability of SKOV-3cells was significantly decreased after 24, 48 and 72hours (P < 0.0001) of either DOX with IC50 22.38, 0.61 and 0.072µg/ml or DOX-NANO treatment with IC50 11.54, 1.01, 0.0126µg/ ml respectively. treatment. Notable decrease in the expression of MDR gene, ABCB1, was observed 48hours after treatment with DOX-NANO (P < 0.0001) with 26% in the assessed with control group. Meta-analysis showed the concentration of 10μg/ml variables was the second most significant feature, whereas the concentration of 0.01μg/ml recognized the lowest weights. Also, LGALS3 is an extra cellular receptor with upregulation in ovarian cancer that interacts with ABCB1. ConclusionOur findings highlight the beneficial effects of DOX delivery in ovarian cancer cells by nanocomposite as efficient drug delivery method. DOX-NANO is a promising therapeutic reagent to overcome chemotherapy resistance in ovarian cancer.

Abstract C023: Overcoming chemotherapy resistance in colombian breast cancer women: Studying gene expression, genetic ancestry, and survival impact on breast cancer response to neoadjuvant treatment response

Abstract C023: Overcoming chemotherapy resistance in colombian breast cancer women: Studying gene expression, genetic ancestry, and survival impact on breast cancer response to neoadjuvant treatment response

Nab-paclitaxel plus S-1 followed by gemcitabine-oxaliplatin as first-line alternating sequential treatment of pancreatic ductal adenocarcinoma.

Alternating sequential administration of drugs may be a promising approach to overcome chemotherapy resistance in advanced pancreatic ductal adenocarcinoma (PDAC). This study was an open-label, single-arm, and prospective trial included patients with untreated advanced PDAC. They received 2 cycles of NS regimen (nab-paclitaxel:125mg/m2, intravenously injected on days 1 and 8, plus S-1:40-60mg, orally twice per day for 1-14 days) followed by 2 cycles of GemOx regimen (gemcitabine, intravenously injected on days 1 and 8, and oxaliplatin: 130mg/m2, intravenously injected on day 1). The primary efficacy endpoint was a progression-free survival rate at 6 months (PFSR-6m). The secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Specific mRNA transcripts were used to explore survival associated genes. Forty-two patients received a minimum of one treatment cycle, and of these, 30 patients completed one alternating treatment consisting of 4 cycles. The PFSR-6m was 71% (95% CI = 58%-87%). The median PFS and OS were 6.53 months (95% CI = 6.03-8.43) and 11.4 months (95% CI = 9.8-14.4), respectively. Common grades 3-4 hematological AEs included neutropenia 30.9%, leukopenia 26.2%, anemia 2.4%, and thrombocytopenia in 11.9%. Patients with OS > 10 months showed high expression of HLA-DQA2 while melanoma-associated antigen genes (MAGE) were notably upregulated in patients with OS < 10 months. The alternating sequential administration of the NS and GemOx regimens may be a novel approach for first-line chemotherapy in patients with advanced PDAC requiring further study (ClinicalTrials.gov Identifier: ChiCTR1900024867).

A carrier-free nanovaccine combined with cancer immunotherapy overcomes gemcitabine resistance

Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.

Inhibition of JAK/STAT3 Expression by Acute Myeloid Leukemia-Targeted Nanoliposome for Chemotherapy Enhancement.

Acute myeloid leukemia (AML) is a relatively common malignant hematological disease whose development is mostly associated with abnormal activation of the JAK/STAT3 signaling pathway. Our previous study revealed that SAR317461, a novel JAK2/STAT3 inhibitor, can effectively inhibit the activation of the JAK2/STAT3 signaling pathway and has significant damaging and pro-apoptotic effects on AML cell lines. This project aims to build upon our prior research to enhance the application of SAR317461 in AML. The surface modification of liposomes with the CD34 antibody, along with the inclusion of the SAR317461 and cytarabine (a common AML chemotherapeutic agent), is observed. Due to the high expression of CD34 on the surface of AML cells, the nanoliposome could target AML cells specifically, further achieving an effective treatment for AML through the synergistic effect of JAK2/STAT3 inhibitors and chemotherapeutic agents. The implementation of this project will provide more theoretical support and ideas for the clinical application of JAK/STAT3 inhibitors in malignant tumors and for overcoming chemotherapy resistance.

The AP-2 Family of Transcription Factors-Still Undervalued Regulators in Gastroenterological Disorders.

Activating enhancer-binding protein 2 (AP-2) is a family of transcription factors (TFs) that play crucial roles in regulating embryonic and oncogenic development. In addition to splice isoforms, five major family members encoded by the TFAP2A/B/C/D/E genes have been identified in humans, i.e., AP-2α/β/γ/δ/ε. In general, the first three TFs have been studied more thoroughly than AP-2δ or AP-2ε. Currently, there is a relatively limited body of literature focusing on the AP-2 family in the context of gastroenterological research, and a comprehensive overview of the existing knowledge and recommendations for further research directions is lacking. Herein, we have collected available gastroenterological data on AP-2 TFs, discussed the latest medical applications of each family member, and proposed potential future directions. Research on AP-2 in gastrointestinal tumors has predominantly been focused on the two best-described family members, AP-2α and AP-2γ. Surprisingly, research in the past decade has highlighted the importance of AP-2ε in the drug resistance of gastric cancer (GC) and colorectal cancer (CRC). While numerous questions about gastroenterological disorders await elucidation, the available data undoubtedly open avenues for anti-cancer targeted therapy and overcoming chemotherapy resistance. In addition to gastrointestinal cancers, AP-2 family members (primarily AP-2β and marginally AP-2γ) have been associated with other health issues such as obesity, type 2 diabetes, liver dysfunction, and pseudo-obstruction. On the other hand, AP-2δ has been poorly investigated in gastroenterological disorders, necessitating further research to delineate its role. In conclusion, despite the limited attention given to AP-2 in gastroenterology research, pivotal functions of these transcription factors have started to emerge and warrant further exploration in the future.

Light-activated hypoxia-sensitive biomimetic decoy efficiently cascading photodynamic-chemo therapy for breast cancer

The hypoxic microenvironment within the tumor microenvironment of breast cancer imposes a challenge in overcoming chemotherapy resistance. In this investigation, we designed a novel strategy utilizing a light-controlled cascade targeting nanomedicine specifically tailored for enhanced immune therapy of breast cancer. Albumin nanoparticle was achieved by crosslinking, followed by loading TPZ and Ce6, and subsequent modification to enable selective binding with CD44 hyaluronic acid to form nanomedicine. Encouragingly, it was demonstrated the remarkable ability of the nanomedicine to effectively internalize into cellular entities, thereby inducing apoptosis in 4T1 cells efficiently in vitro when exposed to light irradiation. In vivo assessments showcased the exceptional aptitude of the nanomedicine not only for preferential accumulation within tumor tissues, but also for substantial suppression of tumor growth. Immune mechanisms have shown that nanomedicine treatment promoted the maturation of DCs in vivo, enhanced the proportion of CD8+ T cells in the spleen and tumor, and simultaneously upregulated the ratio of M1 macrophages favorable for anti-tumor effects. These outcomes collectively advance a fresh perspective for the clinical breast cancer therapy.

Macrophage Migration Inhibitory Factor (MIF) Upregulates CXCR7 and Contributes to Chemotherapy Resistance in Colorectal Cancer.

Colorectal cancer is one of the most common malignant tumors worldwide, with high incidence and mortality rates making it a focus of research. Chemotherapy is a primary treatment modality for colon cancer, but chemotherapy resistance severely impacts treatment efficacy. MIF has been found to promote tumor progression and resistance in various cancers. This study aims to investigate the role of MIF in chemotherapy resistance in colon cancer and its potential mechanisms, particularly through the upregulation of CXCR7 expression, affecting the metabolism and drug sensitivity of colon cancer cells. The expression levels of MIF in colon cancer tissues and its association with patient prognosis were evaluated by analyzing TCGA and HPA data. Subsequently, the expression levels of MIF in colon cancer cell lines and resistant cell lines were detected by qRT-PCR and immunohistochemistry, and the effect of MIF on oxaliplatin sensitivity was assessed. The impact of MIF on the metabolic activity of colon cancer cells was measured using a cellular energy metabolism analyzer. Further experiments explored the mechanism by which MIF affects the metabolic activity of colon cancer cells through the upregulation of CXCR7 expression, and the role of CTCF in regulating CXCR7 transcription was validated by silencing CTCF. Finally, the effect of MIF on drug sensitivity of colon cancer cells was verified in a mouse xenograft tumor model. In this study, we found that the expression of MIF in colon cancer tissues was significantly higher than in normal tissues, and high MIF expression was associated with poor prognosis in patients. The expression levels of MIF in resistant colon cancer cell lines were significantly higher than in parental cell lines, and MIF overexpression significantly increased the resistance of colon cancer cells to oxaliplatin. Conversely, silencing MIF significantly reduced the IC50 value of resistant cells and increased apoptosis. MIF overexpression significantly increased the ECAR and OCR levels of colon cancer cells, while MIF knockdown significantly reduced these metabolic indicators. Further studies indicated that MIF affects the metabolic activity of colon cancer cells by upregulating CXCR7 expression. CTCF binding peaks at the CXCR7 promoter region and luciferase activity assays indicated that CTCF regulates CXCR7 transcription, and silencing CTCF significantly enhanced the sensitivity of colon cancer cells to oxaliplatin. In vivo experiments in mice showed that MIF silencing combined with oxaliplatin treatment significantly inhibited tumor growth and increased the necrotic area of tumor tissues. In conclusion, this study reveals the crucial role of MIF in chemotherapy resistance in colon cancer through the upregulation of CXCR7 expression, with CTCF playing an important regulatory role in this process. Our findings provide new theoretical insights and potential therapeutic targets for overcoming chemotherapy resistance in colon cancer. Future research should further explore the roles of MIF and CXCR7 in other types of cancers and the potential of MIF and CXCR7 as therapeutic targets.

ITGAM sustains MAPK signaling and serves as an adverse prognostic factor and therapeutic target in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the second most frequently occurring type of leukemia in adults. Despite breakthroughs in genetics, the prognosis of AML patients remains dismal. The aim of this study is to find new therapeutic targets and diagnostic markers for AML and to explore their mechanisms of action. The expression patterns of integrin subunit alpha M (ITGAM) were investigated across different cell types using the Human Protein Atlas (HPA) database. The ITGAM levels across cancer types were analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) database. Prognostic correlations in AML individuals were evaluated using The Cancer Genome Atlas (TGCA) database. ITGAM-associated functions were evaluated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The AML cells were transfected with short-hairpin RNA targeting ITGAM or a control, and subsequently subjected to analysis in order to ascertain the impact of ITGAM on proliferation and apoptosis. The expression of ITGAM was significantly higher in the AML patient samples compared to the control samples. High ITGAM expression was significantly associated with poor overall survival (OS). The knockdown of ITGAM in the AML cells resulted in a decrease in proliferation and an increase in apoptosis. This was accompanied by cell cycle arrest at the G1 phase and a downregulation of protein production for cyclin D1, cyclin E1, cyclin-dependent kinase 2 (CDK2), and cyclin-dependent kinase 4 (CDK4). A pathway analysis and a western blot analysis revealed that ITGAM positively regulated mitogen-activated protein kinase (MAPK) signaling by silencing attenuated p38 MAPK (P38), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) phosphorylation, while the total protein levels remained unchanged. ITGAM can serve as a potential prognostic biomarker and therapeutic target for AML. ITGAM production was elevated in AML and indicated poor survival. Silencing ITGAM suppressed AML cell viability and induced apoptosis by blocking cell cycle progression, likely by impeding the activation of the MAPK pathway. Further investigations that directly target the ITGAM-MAPK axis may offer novel strategies for mitigating AML pathogenesis and overcoming chemotherapy resistance.

Mechanism and Potential Therapeutic Strategies Based on PRMT5 in Chemotherapy-Induced Drug Resistance in Non-Small Cell Lung Cancer

As a malignant tumor with high morbidity and mortality in the world, the treatment of non-small cell lung cancer is still facing great challenges. Although new breakthroughs have been made in recent years and great progress has been made in chemotherapy and targeted therapy, the five-year survival rate of most NSCLC patients is still at a low level. The emergence of drug resistance is one of the important factors affecting the therapeutic effect and survival rate of patients. PRMT5 (protein arginine methyltransferase 5), as a type II arginine methyltransferase, plays an important role in cancer cell proliferation, differentiation, apoptosis and tumorigenesis. At present, people pay more and more attention to the research on the mechanism of PRMT5 in tumor drug resistance. In this review, we summarize the mechanism of PRMT5 in chemotherapy resistance of non-small cell lung cancer and discuss potential strategies to avoid or overcome chemotherapy resistance.

Elemene Injection Overcomes Paclitaxel Resistance in Breast Cancer through AR/RUNX1 Signal: Network Pharmacology and Experimental Validation.

Paclitaxel (PTX) is a cornerstone chemotherapy for Breast Cancer (BC), yet its impact is limited by emerging resistance. Elemene Injection (EI) has shown potential in overcoming chemotherapy resistance. However, the efficacy by which EI restores PTX sensitivity in BC and the implicated molecular mechanism remain uncharted. Network pharmacology and bioinformatic analysis were conducted to investigate the targets and mechanisms of EI in overcoming PTX resistance. A paclitaxel-resistant MCF-7 cell line (MCF-7PR) was established. The efficacy of EI and/or PTX in inhibiting cell viability was evaluated using sulforhodamine B assay, while cell proliferation was assessed using EdU staining. Furthermore, protein and gene expression analysis was performed through Western blotting and qPCR. The EI containing three active components exhibited a multifaceted impact by targeting an extensive repertoire of 122 potential molecular targets. By intersecting with 761 differentially expressed genes, we successfully identified 9 genes that displayed a direct association with resistance to PTX in BC, presenting promising potential as therapeutic targets for the EI to effectively counteract PTX resistance. Enrichment analysis indicated a significant correlation between these identified targets and critical biological processes, particularly DNA damage response and cell cycle regulation. This correlation was further substantiated through meticulous analysis of single-cell datasets. Molecular docking analysis revealed robust binding affinities between the active components of the EI and the identified molecular targets. Subsequently, in vitro experiments unequivocally demonstrated the dose- and time-dependent inhibitory effects of the EI on both PTX-resistant and sensitive BC cell lines, effectively mitigating the resistance phenotype associated with PTX administration. Furthermore, our findings have indicated EI to effectively suppress the protein expression levels of AR and RUNX1 in MCF-7 and MCF-7PR cells under PTX treatment, as well as downregulate the mRNA expression levels of stem-like properties' markers, KLF4 and OCT4, in these cell lines. Elemene Injection (EI) application has exhibited a significant capability to mitigate PTX resistance in BC, which has been achieved through targeted suppression of the AR/RUNX1 axis, revealing a key strategy to overcome chemotherapeutic resistance.

Pioneering the Photoactive Relevance of Quinazolinone-Fullereropyrrolidine Nanohybrids To Address Chemotherapeutic Resistance in Cancer.

This study investigates the impact of C70 and C60 fullerenes on quinazolinone, specifically in quinazolinone-fulleropyrrolidine nanohybrids. The nanohybrids Q 3 C 70 M and Q 3 C 60 M exhibit distinct spectral shifts and have significant photobiological antineoplastic properties. Q 3 C 60 M enhances apoptosis, while Q 3 C 70 M reduces Cyclin A levels and counteracts oncogenic effects by promoting cell differentiation. Q 3 C 70 M demonstrates heightened cytotoxicity by overcoming chemotherapy resistance by modulating BAX and BCL-2 levels. This innovative approach, distinguishing between C70 and C60, represents a novel contribution to the existing scientific literature.