Search Results (99)

Background: Chemoresistance and tumor recurrence remain major obstacles in colorectal cancer (CRC) therapy. Elucidating the molecular mechanisms underlying treatment resistance is critical for improving therapeutic outcomes. Methods: We analyzed transcriptomic profiles from public datasets (TCGA and GSE39582) to identify differentially expressed genes associated with a poor response to neoadjuvant chemotherapy in CRC patients. Among 298 candidate genes, ANXA9 emerged as significantly overexpressed in chemoresistant tumors and associated with a poor prognosis. These findings were further validated in an independent cohort of 146 Stage III CRC patients using immunohistochemistry and survival analysis. The expression of ANXA9 was evaluated in oxaliplatin acquired-resistant CRC cell lines via qPCR and Western blot. Functional studies, including RNA interference, colony formation, apoptosis assays, and drug sensitivity testing, were performed in vitro and in vivo to assess the role of ANXA9. A high-throughput drug screen identified G749, a FLT3 inhibitor, as a potential therapeutic agent. Results: ANXA9 expression was significantly elevated in non-responders to chemotherapy and oxaliplatin-resistant CRC cell lines. The knockdown of ANXA9 reduced proliferation and enhanced oxaliplatin sensitivity. G749 was found to suppress ANXA9 expression in a dose-dependent manner and inhibit CRC cell growth in vitro and in patient-derived organoids. In a CRC xenograft mouse model, G749 reduced the tumor burden without observable toxicity. Mechanistically, we identified ZMYM2 as a transcriptional regulator of ANXA9. ChIP-qPCR confirmed ZMYM2 binding to the ANXA9 promoter, especially in resistant cells. Silencing ZMYM2 suppressed tumor cell growth and restored chemosensitivity. Conclusions: The ZMYM2-ANXA9 signaling axis drives chemoresistance and tumor progression in CRC. FLT3 inhibition by G749 effectively downregulates ANXA9 and sensitizes tumors to chemotherapy, highlighting a novel therapeutic approach for chemoresistant CRC. Full article

Hepatocellular carcinoma (HCC) is a lethal malignancy associated with drug resistance, resulting in a poor prognosis. High mobility group box 1 (HMGB1) is a chromatin-binding protein that regulates HCC progression. The overexpression of HMGB1 has been found to promote tumorigenesis and drug resistance. In this study, we aimed to investigate the role of HMGB1 expression in tumorigenesis and metastasis and its impact on sorafenib and oxaliplatin resistance. Tissue samples from patients with HCC (n = 48) were subjected to immunohistochemistry. The expression of HMGB1 was correlated with clinical pathology parameters. Moreover, the HCC cell line HuH-7 was used to study the regulatory effect of HMGB1 on cell proliferation, cell adhesion, migration, and invasion by using the siRNA (small interfering RNA) silencing method. Furthermore, drug challenges were performed to determine the effect of HMGB1 on the sensitivity to chemotherapeutic drugs (sorafenib and oxaliplatin). HMGB1 was significantly overexpressed in tumor tissues, highlighted by the expression increment in patients with M1 advanced metastasis tumors with immunoreactivity scores 2.61 and 6.50 for adjacent and tumor tissues, respectively (p-values = 0.0035). The involved mechanisms were then described through the suppression of HCC cell adhesion, migration, and invasion by HMGB1 silencing. Notably, the inhibition of HMGB1 expression promoted sorafenib/oxaliplatin sensitivity in the HCC cell line by increasing the cell toxicity by about 13–18%. Our study demonstrated that HMGB1 shows potential as a promising biomarker and a target for HCC treatment that is involved in tumorigenesis, metastasis, and chemo-drug resistance. Full article

The treatment landscape of metastatic colorectal cancer (mCRC) has undergone significant evolution, with the introduction of targeted therapies and immunotherapy dramatically altering the management of microsatellite instability-high (MSI-H) tumors. However, the majority of patients, particularly those with microsatellite-stable (MSS) disease, remain refractory to immunotherapy, necessitating the exploration of alternative therapeutic strategies. This review summarizes the current treatment options for heavily pretreated mCRC patients who are not eligible for targeted therapies or clinical trials. Approved therapies for refractory mCRC, including regorafenib, trifluridine/tipiracil (FTD/TPI), and fruquintinib, demonstrate modest survival benefits but are often associated with significant toxicities. Additionally, innovative approaches targeting specific mutations such as KRAS G12C, HER2 amplification, and BRAF V600E are discussed, highlighting emerging combination regimens with immune checkpoint inhibitors and other agents to overcome resistance mechanisms. The potential of rechallenge strategies using previously administered therapies, such as oxaliplatin and anti-EGFR agents, is examined, supported by retrospective and prospective studies. Furthermore, the role of older drugs like mitomycin C in combination with capecitabine is revisited, offering insights into their viability in advanced treatment settings. Ongoing clinical trials with novel agents and combinations are expected to provide further clarity on optimizing sequential treatment regimens and personalizing therapy for mCRC patients. This review emphasizes the need for comprehensive molecular profiling and shared decision-making to improve outcomes and quality of life in this challenging patient population. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, necessitating the continuous evolution of therapeutic approaches. Despite advancements in early detection and localized treatments, metastatic colorectal cancer (mCRC) poses significant challenges due to low survival rates and resistance to conventional therapies. This review highlights the current landscape of CRC treatment, focusing on chemotherapy and targeted therapies. Chemotherapeutic agents, including 5-fluorouracil, irinotecan, and oxaliplatin, have significantly improved survival but face limitations such as systemic toxicity and resistance. Targeted therapies, leveraging mechanisms like VEGF, EGFR, and Hedgehog pathway inhibition, offer promising alternatives, minimizing damage to healthy tissues while enhancing therapeutic precision. Furthermore, future directions in CRC treatment include exploring innovative targets such as Wnt/β-catenin, Notch, and TGF-β pathways, alongside IGF/IGF1R inhibition. These emerging strategies aim to address drug resistance and improve patient outcomes. This review emphasizes the importance of integrating molecular insights into drug development, advocating for a more personalized approach to combat CRC’s complexity and heterogeneity. Full article

Chemotherapy for cancer frequently uses platinum-based medications, including oxaliplatin, carboplatin, and cisplatin; however, due to their high systemic toxicity, lack of selectivity, drug resistance, and other side effects, platinum-based medications have very limited clinical application. As a first-line medication in antitumor therapy, oxaliplatin must be administered to minimize side effects while achieving anticancer objectives. A new CDC7 inhibitor called XL413 has demonstrated promising antitumor therapeutic effects in a variety of malignant tumors and may have anticancer properties. This offers a fresh viewpoint on how to lessen oxaliplatin resistance and, specifically, increase the potency of already prescribed anticancer therapies. In this paper, the current developments in anticancer therapy are discussed, along with the many mechanisms of oxaliplatin’s antitumor effects, clinical treatment challenges, and related approaches. We conducted more research on oxaliplatin resistance that arose during chemotherapy and searched for ways to lessen it in order to enhance its chemotherapeutic performance. Ultimately, we studied how distinct resistance routes relate to one another. Meanwhile, XL413, a novel CDC7 inhibitor, offers a perspective on the possibilities for developing treatment approaches for this innovation point. The search terms “Oxaliplatin, XL413, drug resistance, cancer treatment,” etc., were applied in the X-MOL and PubMed databases for this review’s literature search. Boolean logic was then employed to maximize the search approach. These databases can offer thorough research data and cover a broad range of biological publications. Excluded publications were works of low relevance, duplicates, or those with insufficient information. The mechanism of oxaliplatin’s anticancer effect, oxaliplatin resistance and its amelioration, and the role of XL413 in oxaliplatin treatment were the main topics of the 140 publications that were ultimately included for analysis. Full article

Background: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) using the original 30 min protocol has shown limited benefits in patients with peritoneal metastasis of colorectal cancer (PMCRC), likely due to the short duration, which limits drug penetration into tumor nodules. Bevacizumab, an antiangiogenic antibody that modifies the tumor microenvironment, may improve drug delivery during HIPEC. This in silico study evaluates the availability of oxaliplatin within tumor nodules when HIPEC is performed after bevacizumab treatment. Methods: Using a computational fluid dynamics (CFD) model of HIPEC, the temperature and oxaliplatin distribution within the rat abdomen were calculated, followed by a model of drug transport within tumor nodules located at various sites in the peritoneum. The vascular normalization effect of the bevacizumab treatment was incorporated by adjusting the biophysical parameters of the tumor nodules. The effective penetration depth values, including the thermal enhancement ratio of cytotoxicity, were then compared between HIPEC alone and HIPEC combined with the bevacizumab treatment. Results: After bevacizumab treatments at doses of 0.5 mg/kg and 5 mg/kg, the oxaliplatin availability increased by up to 20% and 45% when HIPEC was performed during the vascular normalization phase, with the penetration depth increasing by 1.5-fold and 2.3-fold, respectively. Tumors with lower collagen densities and larger vascular pore sizes showed higher oxaliplatin enhancement after the combined treatment. Bevacizumab also enabled a reduction in the oxaliplatin dose (up to half at 5 mg/kg bevacizumab) while maintaining effective drug levels in the tumor nodules, potentially reducing systemic toxicity. Conclusions: These findings suggest that administering oxaliplatin-based HIPEC during bevacizumab-induced vascular normalization could significantly improve drug penetration and enhance treatment efficacy. Full article

Background/Objectives: Metastatic colorectal cancer (mCRC) is mainly treated with 5-Fluoro-Uracil (5-FU), Oxaliplatin and Irinotecan chemotherapies and anti-Epidermal Growth Factor Receptor (EGFR) or anti-Vascular Endothelial Growth Factor (VEGF) targeted therapies. Due to chemotherapy-related toxicity, patients receive induction treatment to achieve tumour response followed by maintenance therapy with less cytotoxic molecules or a chemotherapy-free interval to reduce chemotherapy-related toxicity. In this study, the aim was to determine the patient, cancer and treatment factors that influence the duration of maintenance therapy (DMT). Methods: We collected retrospective data on a cohort of 133 patients treated at the Centre Georges François Leclerc (CGFL) cancer centre in Dijon between March 2014 and June 2022. Patients had unresectable or potentially resectable diseases. They received first-line induction treatment with chemotherapy and/or targeted therapy and maintenance treatment, defined as the interruption of at least one chemotherapy agent. Results: In the multivariate analysis, age (HR: 1.02, 95% CI 1.00–1.04, p = 0.031), N2 nodal status (HR: 1.78, 95% CI 1.09–2.89, p = 0.021) and the presence of peritoneal metastases (HR: 2.05, 95% CI 1.25–3.36, p = 0.004), as well as baseline carcino-embryonic antigen (CEA) level (HR: 1.10, 95% CI 1.00–1.20, p = 0.052), were significantly associated to poor DMT. Local treatment of liver metastases also significantly reduced the DMT (HR: 0.49, 95% CI 0.28–0.86, p = 0.013). In our cohort, induction triplet chemotherapy significantly increased the CEA delta (70% vs. 44%, p = 0.047) compared to doublet chemotherapy and led to a higher rate of liver surgery (40% vs. 21%, p = 0.014) and a trend for a higher rate of local treatment of metastases (62% vs. 45%, p = 0.059). Conclusions: Duration of maintenance therapy is determined by the initial patient and colorectal cancer characteristics. However, it is significantly increased by local treatment of liver metastases. By reducing the tumour burden, a triplet induction chemotherapy regimen increases the rate of liver metastase resection. Full article

Background: Chemotherapy-induced peripheral neuropathy (CIPN) from oxaliplatin and taxane drugs is a bothersome toxicity. Palmitoylethanolamide (PEA) has been reported to improve myelinated nerve fiber function in patients experiencing painful CIPN. We conducted a double-blind, placebo-controlled, randomized trial of PEA in patients with established CIPN. Methods: Eligible patients were adults who had pain, numbness, tingling, or other symptoms of CIPN for at least three months following completion of paclitaxel, oxaliplatin, or cisplatin-based chemotherapy. Study patients were randomized to one of the two treatment groups (PEA versus placebo, both administered either once or twice daily). The CIPN20 questionnaire was assessed weekly. Results: A total of 17 males and 71 females participated in the study; most had neuropathy from paclitaxel. Most (85%) finished 8 weeks of treatment. There was no suggestion that either of the PEA arms did any better than the combined placebo arms. There was no signal of significant toxicity differences between the three study arms. Quality of life outcome measures were similar between the study arms, as were cognitive function evaluations. Discussion: PEA failed to improve established CIPN. Future trials might explore whether PEA may be effective in preventing CIPN or cognitive changes based on data that suggest it may be helpful in this situation. Conclusions: PEA failed to improve established chemotherapy-induced neuropathy. Full article

Capecitabine (CAP) is one of the most commonly prescribed fluoropyrimidines in oncology, especially in the treatment of colon cancer. Cardiac toxicity is a severe and potentially lethal adverse drug reaction (ADR) against fluoropyrimidines. Cardiac ADRs, such as myocardial infarction (MI), heart failure (HF), arrhythmias, and a number of cardiomyopathies, are reported for these molecules. To have a better understanding of the risk–benefit ratio of colon cancer therapy, a pharmacovigilance study of real-world evidence of the cardiac toxicity of antineoplastic agents is required. Aim: This post-marketing research on CAP aims to assess the risk of cardiac toxicity. Five other antitumor drugs used in colorectal cancer, i.e., 5-fluorouracil (5-FU), irinotecan (IRI), oxaliplatin (OX), bevacizumab (BEV) and panitumumab (PAN), were also studied to create a relative profile of observed cardiotoxicity. Methods: A retrospective study based on reports submitted in the EudraVigilance (EV) database until 28 July 2024 was conducted. Using the aggregated data from EV, a descriptive analysis and disproportionality analysis of cardiac ADRs induced by fluoropyrimidines were performed. To evaluate the disproportionality of the signals, Reporting Odds Ratio (ROR) and 95% confidence interval (95% CI) were calculated by comparison with other drugs used in colorectal cancer: 5-FU, IRI, OX, BEV, and PAN. Results: “Cardiac disorders” represent 3.4% of the total reports for CAP. The value is comparable to 5-FU, but higher than for other drugs. t was observed that there are no significant differences in the occurrence of cardiac ADRs in patients exposed to CAP and 5-FU treatments, and in particular MI and HF. Compared to 5-FU, which could produce cardiac arrythmias with a higher probability than all other drugs, CAP has a higher probability of reporting this ADR only in comparison with IRI (ROR: 1.2971; 95% CI: 1.0196-1.6502). Conclusions: CAP induces adverse cardiovascular reactions, especially MI, HF, and cardiomyopathies. Arrhythmias have been shown to be side effects more frequent associated with 5-FU than with CAP. The results emphasize the need for a rigorous cardiovascular monitoring of patients following treatment with CAP or 5-FU and especially for those with pre-existing cardiac pathology. Full article

The search for new antineoplastic agents is imperative, as cancer remains one of the most preeminent causes of death worldwide. Since the discovery of the therapeutic potential of cisplatin, the study of metallodrugs in cancer chemotherapy acquired increasing interest. Starting from cisplatin derivatives, such as oxaliplatin and carboplatin, in the last years, different compounds were explored, employing different metal centers such as iron, ruthenium, gold, and palladium. Nonetheless, metallodrugs face several drawbacks, such as low water solubility, rapid clearance, and possible side toxicity. Encapsulation has emerged as a promising strategy to overcome these issues, providing both improved biocompatibility and protection of the payload from possible degradation in the biological environment. In this respect, liposomes, which are spherical vesicles characterized by an aqueous core surrounded by lipid bilayers, have proven to be ideal candidates due to their versatility. In fact, they can encapsulate both hydrophilic and hydrophobic drugs, are biocompatible, and their properties can be tuned to improve the selective delivery to tumour sites exploiting both passive and active targeting. In this review, we report the most recent findings on liposomal formulations of metallodrugs, with a focus on encapsulation techniques and the obtained biological results. Full article

Gastrointestinal (GI) toxicity is a common side effect in patients undergoing oxaliplatin (OxPt)-based chemotherapy for colorectal cancer (CRC). Frequently, this complication persists in the long term and could affect the efficacy of the treatment and the patient’s life quality. This long-term GI toxicity is thought to be related to OxPt-induced enteral neuropathy. AmotL2 is a member of the Angiomotin family of proteins, which play a role in cell survival, neurite outgrowth, synaptic maturation, oxidative stress protection, and inflammation. In order to assess the role of AmotL2 in OxPt-induced enteral neuropathy, we studied the expression of AmotL2 in cells of the enteric nervous system (ENS) of untreated and OxPt-treated CRC patients and its relationship with inflammation, using immunofluorescence confocal microscopy. Our results in human samples show that the total number of neurons and glial cells decreased in OxPt-treated patients, and TNF-α and AmotL2 expression was increased and colocalized in both neurons and glia. AmotL2 differential expression between OxPt-treated and untreated CRC patients shows the involvement of this scaffold protein in the inflammatory component and toxicity by OxPt in the ENS. Full article

Background: This was an observational study prospectively evaluating the effectiveness and safety of aflibercept/FOLFIRI administered in second-line mCRC per the reimbursement criteria in Poland. Methods: Consecutive mCRC patients who progressed with first-line oxaliplatin-based chemotherapy received aflibercept (4 mg/kg IV) followed by FOLFIRI every 2 weeks until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); overall survival (OS) and safety were the secondary endpoints. Results: A total of 93 patients were treated at 17 Polish sites. A median of 10 cycles was administered. Over a median treatment duration of 5.3 months, median PFS and median OS were 8.4 months [95% CI, 6.9–9.9] and 27.0 months [95% CI, 23.9–30.1], respectively. There was no significant impact of primary tumor location, metastatic site, or KRAS status on PFS and OS. Main grade ≥ 3 adverse events were neutropenia (16%), hypertension (8%), diarrhea (4%), and stomatitis (4%). Conclusions: The benefits/risks of Aflibercept plus FOLFIRI administered per the Polish reimbursement criteria in second-line treatment of mCRC after failure of a prior oxaliplatin-based regimen is confirmed. Full article

Chemotherapeutic drugs are indispensable in cancer treatment, but their effectiveness is often lessened because of non-selective toxicity to healthy tissues, which triggers inflammatory pathways that are harmful to vital organs. In addition, tumors’ resistance to drugs causes failures in treatment. Chlorogenic acid (5-caffeoylquinic acid, CGA), found in plants and vegetables, is promising in anticancer mechanisms. In vitro and animal studies have indicated that CGA can overcome resistance to conventional chemotherapeutics and alleviate chemotherapy-induced toxicity by scavenging free radicals effectively. This review is a summary of current information about CGA, including its natural sources, biosynthesis, metabolism, toxicology, role in combatting chemoresistance, and protective effects against chemotherapy-induced toxicity. It also emphasizes the potential of CGA as a pharmacological adjuvant in cancer treatment with drugs such as 5-fluorouracil, cisplatin, oxaliplatin, doxorubicin, regorafenib, and radiotherapy. By analyzing more than 140 papers from PubMed, Google Scholar, and SciFinder, we hope to find the therapeutic potential of CGA in improving cancer therapy. Full article

Efforts to improve the prognosis for patients with locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma have focused on neoadjuvant approaches to increase the pathological complete response (pathCR) rate, improve surgical resection, and prolong event-free and overall survival (OS). Building on the recent evidence that PD-1 inhibition plus chemotherapy improves the OS of patients with metastatic GEJ adenocarcinoma, we evaluated whether the application of this strategy in the neoadjuvant setting would improve the pathological response. This single-center phase I/II trial evaluated the safety, toxicity, and efficacy of neoadjuvant atezolizumab with oxaliplatin and 5-fluorouracil (modified FOLFOX) followed by esophagectomy followed by atezolizumab. The primary objective goal was to achieve 20% pathCR. From the twenty enrolled patients, eighteen underwent resection and two (10%, 95% CI: 1.24–31.7%) achieved pathCR. After a median follow-up duration of 40.7 months, 11 patients had disease recurrence and 10 had died. The median disease-free and OS were 28.8 (95% CI: 14.7, NA) and 38.6 months (95% CI: 30.5, NA), respectively. No treatment-related adverse events led to death. Although modified FOLFOX plus atezolizumab did not achieve the expected pathCR, an acceptable safety profile was observed. Our results support the continued development of a more refined strategy (neoadjuvant chemotherapy plus perioperative immunotherapy/targeted agents) with molecular/immune profiling in parallel. Full article