Artesunate (ART), a well-established antimalarial agent, has demonstrated promising anticancer activity in both in vitro and in vivo studies. Despite its potential, clinical application of ART in oncology is limited by modest efficacy and dose-limiting toxicity, likely due to nonspecific accumulation in normal tissues. Targeted delivery strategies are therefore essential to enhance therapeutic selectivity and reduce off-target effects. To this end, ART has been conjugated with targeting molecules such as aptamers, dyes, and polymers. DZ-1, a heptamethine cyanine dye, selectively accumulates in cancer cells through overexpression of organic anion transporting polypeptides (OATPs), offering a promising vehicle for tumor-specific delivery. In this study, we evaluated the anticancer efficacy and underlying mechanisms of a novel conjugate of DZ-1 and ART (DZ-1-ART) in three human cancer cell lines: colon cancer (HCT116), pancreatic cancer (BxPC-3), and breast cancer (MCF-7). DZ-1-ART induced time-dependent cytotoxicity across all tested cancer cell lines. Mechanistically, DZ-1-ART localized to both mitochondria and lysosomes, but functional studies indicated that lysosomes were not essential for its pro- apoptotic activity. Instead, DZ-1-ART triggered mitochondria-mediated apoptosis via a Bid-, Bax-, and Bak-independent pathway, leading to caspase-3 activation and cell death. Our findings demonstrate that DZ-1-ART undergoes intracellular trafficking through lysosomes and mitochondria, but induces apoptosis primarily through a mitochondrial, Bid-Bax/Bak- independent, caspase-3-dependent pathway. These results support the development of DZ-1- ART as a tumor-targeted anticancer agent with potential applications in theranostics.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising cytokine that selectively targets cancer cells while sparing normal tissues. Despite its favorable safety profile, clinical trials have demonstrated antitumor responses in only a small subset of patients. This limited efficacy has been largely attributed to the short plasma half-life of recombinant monomeric soluble TRAIL (rhTRAIL). To enhance its stability and therapeutic potential, researchers have developed modified versions, including an immunoglobulin Fc domain-fused TRAIL (Fc-TRAIL) and a dimeric Fc-fused single-chain variant (Fc-scTRAIL). In this study, we used the SNU-1746 three-dimensional (3D) multicellular layer culture model and a patient-derived colon cancer tumoroid model to evaluate the biological activity of these TRAIL formats (rhTRAIL, Fc-TRAIL, and Fc-scTRAIL). Treatment with rhTRAIL revealed that a longer exposure time (18-24 hours) was required to induce apoptosis in both 3D models, in contrast to monolayer cultures. Among the TRAIL formats, Fc-scTRAIL was the most potent in inducing apoptosis, as confirmed by immunoblotting analyses. Furthermore, artesunate (ART) enhanced TRAIL-induced apoptosis across all TRAIL formats, with the strongest synergistic effect observed in combination with Fc-scTRAIL. JC-1 staining assays indicated that mitochondrial membrane depolarization (a hallmark of the intrinsic apoptosis pathway) plays a key role in the cell death observed with the combination treatment in tumoroids. These findings provide compelling preclinical evidence supporting the potential of ART and Fc-scTRAIL combination therapy for future clinical evaluation.
Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. While chemo- and radiotherapy are often effective in treating newly diagnosed GBM, increasing evidence suggests that treatment-induced metabolic alterations promote tumor recurrence and further resistance. In addition, GBM tumors are typically hypoxic, which further contributes to treatment resistance. Recent studies have shown that changes in glioma cell metabolism driven by a shift in the isoform expression of mitochondrial cytochrome c oxidase (CcO) subunit 4 (COX4), a key regulatory subunit of mammalian CcO, may underlie the treatment-induced metabolic alterations in GBM cells. However, the impact of hypoxia on GBM energetics is not fully understood. Using isogenic GBM cell lines expressing either COX4-1 or the alternative COX4 isoform, COX4-2, we found that COX4-1 expressing cells maintained a more oxidative metabolism under hypoxia, characterized by increased CcO activity and ATP production, enhanced assembly of CcO-containing mitochondrial supercomplexes, and reduced superoxide production. Furthermore, COX4-1 expression was sufficient to increase radioresistance under hypoxic conditions. Untargeted metabolomic analysis revealed that the most significantly upregulated pathways in COX4-1-expressing cells under hypoxia were purine and methionine metabolism. In contrast, COX4-2-expressing cells showed increased activation of glycolysis and the Warburg effect. Our study provides new insights into how CcO regulatory subunits influence cellular metabolic networks and radioresistance in GBM under hypoxia, identifying potential therapeutic targets for improved treatment strategies.
Sphingolipids are a class of bioactive lipids which are highly involved in cellular functions such as signaling, membrane composition, and determining cell fate. The metabolism of these lipids plays important roles in the development and progression of many diseases such as cancer. The role of sphingolipid metabolism in cancer overall is not yet fully understood. However, key sphingolipids such as sphingosine-1-phosphate (S1P) and ceramide have been shown to be influential on the death or survival of cancer cells. S1P is known to exert pro-survival signaling effects when expressed at higher levels in cells. Ceramide, on the other hand, has been established as a pro-death lipid, regulating apoptosis, cell cycle arrest, autophagy, and mitophagy. Cancer cells are typically characterized by an increased ratio in S1P to ceramide, thus granting the survival of the cancer. This ceramide/S1P biostat is the target of many new therapeutics which aim to increase ceramide levels in cancer cells. Additionally, many previously established drugs have been rediscovered for their unexpected ability to perturb sphingolipid metabolism. This review serves to summarize the current use of ceramide and sphingolipid metabolism-related therapies for the treatment of many cancers.
Despite extensive efforts, glioblastoma multiforme (GBM), the most malignant brain cancer, continues to pose significant challenges to effective treatment, with limited progress in patient survival over the last three decades. This study addresses shortcomings of conventional therapies, particularly radiotherapy (RT), which faces limitations due to radio-resistance and toxic radiation doses. Boron neutron capture therapy (BNCT) is a promising alternative, delivering targeted radiation to tumor cells with minimal damage to healthy tissue. However, the key challenge lies in achieving sufficient boron uptake selectively in tumor cells. We have developed a novel nanomedicine-based approach, utilizing polymalic acid (PMLA) as a delivery vehicle, carrying multiple boron-10 molecules per nanoconjugate to increase the intracellular concentration of boron-10 for effective boron neutron capture therapy. Our novel nanodrug (Nano-Boron) incorporates isotopically enriched 4-boronophenylalanine (BPA) as a source of boron-10 and Angiopep-2 (AP2) peptide for blood-brain barrier penetration and tumor targeting. The PMLA platform allows for the attachment of a large quantity of boron-10, enhancing the intracellular boron concentration and, consequently, the efficacy of BNCT. This innovative approach holds the potential to address the unmet clinical need in GBM treatment and improve patient survival and quality of life.
Background: Although thermal imaging has been tried in medical practice before, its use in gynaecological oncology is not established in practice yet. Objectives: To assesses the feasibility of thermal imaging (infrared technology) for tumour detection during gynaecological oncological surgeries, and to explore the feasibility of enhancing surgical outcomes by using thermal camera. Methods: This prospective feasibility study was conducted at a London tertiary cancer centre in the period between September 2022 and September 2023. Preoperative and intraoperative thermal images were captured using a Flir One Pro smartphone thermal camera. Subsequent images analysis was performed to correlate temperature and colour variations to tumour presence. Results: Thermal images were captured for 26 patients. Thermal imaging was able to identify malignant tumours close to abdominal wall in 73.6% of the cases, with a sensitivity of 93.3% and a positive predictive value of 77.8%. Among these, seven patients were excluded due to suboptimal imaging quality. The technique was able to map tumour locations relatively accurately. (4) Conclusion: Thermal imaging presents a promising non-invasive approach for tumour localization in gynaecological oncology. It offers significant potential to improve surgical precision and possibly patient outcomes. Thermal could serve as a valuable adjunct to conventional diagnostics in gynaecological oncology patients. Further validation by larger studies using more advanced thermal imaging is still required before we can generalize these findings in clinical practice.
Non-small cell lung cancer (NSCLC) remains a prevalent and deadly malignancy, presenting a substantial global health challenge. Significant progress has been achieved in the last few decades regarding the comprehension of the complex molecular mechanisms that underlie NSCLC. This extensive literature review analyzes the present understanding of the molecular pathways associated with non-small cell lung cancer (NSCLC) and emphasizes the potential of molecular targeting as a favorable therapeutic approach. We conduct a detailed analysis of key molecular targets and discuss the impact of emerging therapeutic modalities on the treatment landscape of NSCLC. Furthermore, we explore potential avenues for future research in this rapidly advancing field, emphasizing the importance of ongoing research and innovation in managing NSCLC and advancing precision medicine.
Lung cancer continues to be a significant global health challenge, characterized by high mortality rates and limited treatment options in its advanced stages. However, the advent of immunotherapy has begun to transform the therapeutic landscape, offering new hope for pa-tients. This paper aims to provide a detailed analysis of the current state and prospects of im-munotherapy in the management of lung cancer. Specifically, it will offer a comprehensive his-torically review of recent clinical trials, emerging immunotherapeutic agents, predictive bi-omarkers, and novel targets for non-small cell lung cancer from the development of immuno-therapy for metastatic lung cancer to advances in immunotherapy in the neoadjuvant and ad-juvant setttings. Moreover, the paper will explore the challenges and opportunities associated with immunotherapy, including resistance mechanisms and the potential of combination ther-apies. Through this analysis, the paper intends to underscore the revolutionary impact of im-munotherapy on lung cancer treatment, advocating for the advancement of more personalized and efficacious therapeutic strategies.
Gemcitabine was shown to augment anti-cancer activity when combined with small molecule CHK1 inhibitors. We had previously demonstrated that we could incorporate gemcitabine molecules into the backbone of an siRNA targeting CHK1 and studied this drugs effects in pancreatic cancer cells [1]. We had optimized the number of gemcitabines to improve efficacy in the combination where the CHK1 siRNA was unmodified [1]. In this manuscript, we extend these studies by using chemically modified siRNAs using the same siRNA sequence targeting CHK1. We varied the 2'-Fluoro and 2'-O-Methyl modification patterns within the sequence, with gemcitabines in the same locations within the same siRNA sequence. We show that adding gemcitabines into the siRNA can demonstrate improved potency, not only against pancreatic cancer cell models but also against lung cancer, ovarian cancer, triple negative breast cancer and colon cancer. We formulated the different versions of CHK1 siRNA + gemcitabine into polypeptide nanoparticles with good control over size (~82-88nm) and zeta potential (34-36mV). When delivered intravenously to mice bearing a pancreatic xenograft tumor, the cocktail showed a reduction in tumor burden. The product demonstrated inhibitory effects in vivo, with no effect on the body weights of the animals. We further examined the ability to improve on the potency of this reagent by inclusion of a second siRNA (targeting WEE1) and demonstrate that, in vitro, the pancreatic cancer cell line, MiaPaca2, is particularly sensitive to a combo of CHK1 siRNA plus gemcitabine together with a second siRNA against WEE1.
Background: Thymus epithelial neoplasms are rare tumors, with a reported incidence of 0.13:100,000 person/year. The basis of treatment is surgical and postoperative radiotherapy has shown improvement in overall survival. In case of being unresectable, the therapy of choice would be systemic. Due to the frequency of the disease, there are few studies to help us regulate our behavior. Our objective is To identify and describe the characteristics and the oncological results of this tumors. Methods: Retrospective, descriptive and analytical cohort study, conducted in a single center. A descriptive and exploratory analysis was done to know the behavior of the data. For survival analysis, Kaplan - Meier curves and Log Rank analysis were used. Univariate and multivariate analyses were performed. Results: in a period of 10 years, a sample of 18 patients was obtained. 17% were carcinomas and the rest thymomas. The median survival was 36.9 months; for thymoma 62.3 and carcinoma 27.2 (p=0.04). In relation to the clinical stages of both Masaoka and TNM, had a mean survival of 90.8 months for localized or crazy advanced stages, and 33.8 for stage IV (p = 0.022). Conclusions: In Mexico there is lack of information regarding these neoplasms. We found 18 cases, the characteristics of the cases have similarities in relation to other works. In the survival analysis we found higher risk to higher clinical stage, both Masaoka and TNM and histology of the WHO. We present one of the first cohorts of thymus epithelial tumors in Mexico.
Purpose : Multimodal treatments for ovarian cancer (OC) and endometrial cancer (EC) are susceptible to induce long-term disorders and to alter the quality of life of patients. This review aims to underlines the necessity to move forward to better identify and manage the sides effects and sequelae in order to enhance quality of life of gynecological cancer survivors. Methods : narrative review. Results : OC and EC patients experience a wide range of symptoms that may persist over time: fatigue, pain, nausea, abdominal discomfort, peripheral neuropathy, anxiety, depression , sleep disorders, menopausal symptoms and sexual disorders. Management of these disorders need to be included in follow-up care plans that help to summarize cancer history, long-term side effects and to give information on health promotion and prevention. Long term patient-reported outcome measures may contribute to cover the full range of these toxicities such as fatigue, lymphedema, and cognitive impairment. The coordination between the supportive care and the health-care provider is crucial needed to offer a personalized management for OC and EC survivors and to ensure adapted supportive care along survivorship. Conclusion: Gynecological cancer survivors have specific needs that should be addressed systematically by caregivers. The implementation of a survivorship care plan after cancer treatment is recommended and can be useful to monitor patient's needs. Coordination and development of networks of supportive care providers for long-term survivors after gynecological cancer is needed to reduce long-term toxicities and improve the quality of life of these patients.
Introduction: The ABO is still the most important blood group system in transfusion and transplantation therapy. ABH antigens are the product of gene combinations at three different loci (ABO, Hh, and Se) and produce certain glycosyltransferases for oligosaccharide precursor chain with monosaccharides at specified linkages, where the terminal sugar influences antigen specificity. Exons 6 and 7 are the longest coding region providing the catalytic domain for the ABO glycosyltransferases. The substitution of amino acid within exons 6 and 7 coding regions of ABO glycosyltransferases is responsible for ABO groups/ subgroups determination.
A 79-year-old male patient was referred to our healthcare facility because of an abnormal CT shadow detected during follow-up of prostatectomy. The nodules revealed a tendency of increasing in size, and primary lung cancer was suspected. The patient underwent a right lower lobectomy and mediastinal lymphadenectomy via video-assisted thoracic surgery. As there was no evidence of primary disease in other organs, we diagnosed the patient with primary malignant melanoma of the lungs (PMML). Postoperative pathological examination revealed no lymph node metastasis. However, bronchoscopy revealed slight brownish-toned changes in the resection margins of the right lower lobe of the bronchus. Biopsies of the resected margins confirmed the presence of malignant melanoma cells. Owing to the presence of BRAF mutated cells in the surgical specimen, dabrafenib/trametinib treatment was initiated. Subsequent bronchoscopy revealed new brownish-toned changes in the bronchial mucosa from the trachea to the right bronchus, suggesting malignant melanoma. The patient underwent regular bronchoscopic examinations from that time with no major deterioration and is still undergoing treatment. Although PMML has a poor prognosis, in this case, disease control was achieved over a long period through molecular targeted therapy for the BRAF mutation, and bronchoscopy was useful in determining the therapeutic effects.
We present a case of a 77-year-old female who was diagnosed with right breast invasive carcinoma treated with breastconserving surgery and adjuvant radiation therapy in 2015. In 2023, she was diagnosed with radiation-induced angiosarcoma (RIAS), and a right breast mastectomy was recommended. RIAS is difficult to diagnose due to its rarity and non-specific symptoms. This paper examines various factors causing RIAS and strategies to manage this disease. Even though achieving clear margins is challenging due to its multifocal nature, surgical resection remains the primary treatment for RIAS. The role of chemotherapy remains unclear, although targeted therapies may offer alternative options. The prognosis for RIAS is influenced by factors including the size of the tumor and stage at diagnosis. Adjuvant chemotherapy’s role is still evolving, and developments within radiotherapy approaches have allowed for enhanced local control. Further research is required to develop optimal treatment protocols and preventive strategies.
Background: Head and neck squamous cell carcinoma (HNSCC) generally begins in the squamous cells of the head and neck mucosal surfaces, and are the sixth most common cancers worldwide. The leaf extract of Osmanthus heterophyllus contains lignans and secoiridoids, which have various biological activities including anticancer activity. This study aimed to investigate the potential anticancer effects of O. heterophyllus leaf extract on HNSCC FaDu cells and its underlying mechanism. Methods: The extract of O. heterophyllus leaves was obtained using a Dionex™ ASETM 350 Accelerated Solvent Extractor. After treating FaDu cells with the extract for 24 h, cell viability was evaluated using an MTT assay, and apoptosis-related proteins, mammalian target of rapamycin (mTOR) phosphorylation, and cytokeratin (CK) 18 expression were detected by western blotting. Cells were stained with an Annexin-V/PI double-staining assay using an Arthur image-based cytometric assay. Results: O. heterophyllus ethanol extract (OHEE) significantly reduced FaDu cell viability, increased cleaved caspase 3 and PARP, and also increased Annexin-V/PI double-stained cells. The expression of CK18 by OHEE increased while that of phospho-mTOR decreased, and the expression of CK18 decreased when mTOR phosphorylation was restored by glucose. Conclusions: OHEE induces apoptosis in HNSCC FaDu cells, which is associated with the regulation of mTOR and CK18.
Purpose of Review: Richter's syndrome (RS) is an aggressive lymphoma that arises from pre-existing chronic lymphocytic leukemia (CLL). Despite significant advancements in CLL treatments over the last decade, including the emergence of novel therapies, RS continues to be associated with poor outcomes. In this review, we examine the current literature on RS and discuss the future research direction. Recent Findings: Traditional chemoimmunotherapy regimens in RS have been associated with generally poor outcomes. However, encouraging data emerged with the CAR-T cellular therapies, the CD20/CD3 bispecific antibodies and the combination of novel agents with chemoimmunotherapy. Summary: Richter's syndrome remains a therapeutic challenge with limited standard-of-care options. Advances in understanding its pathogenesis and the development of novel therapies hold promise for improving outcomes. Collaboration and ongoing clinical trials are essential to enhance treatment strategies for this aggressive complication of CLL.
Purpose: The promise of immune checkpoint inhibitor (ICI) therapy underlines the importance of comprehensively investigating the rationale for combinations with diverse immune modulators across different cancer types. Given the progress made with PD1 blockade to date, we examined mRNA co-expression levels of PD-1 with 13 immune checkpoints, including co-inhibitory receptors (LAG3, CTLA4, PD-L1, TIGIT, TIM3, VISTA, BTLA) and co-stimulatory molecules (CD28, OX40, GITR, CD137, CD27, HVEM), using RNA-Seq by Expectation-Maximization (RSEM). Methods: We analyzed real-world clinical and transcriptomic data from the Total Cancer Care Protocol (NCT03977402) and Avatar® project of patients with cancer treated within the Oncology Research Information Exchange Network (ORIEN) network. Using anti-PD1 as a backbone, we intended to investigate the rationale for combinations in different cancers. Pearson's R coefficients and associated P-values were calculated using SciPy 1.7.0. Results: The co-expression of PD1 with 13 immune checkpoints and PD-L1 varies across selected malignancies included. In cutaneous melanoma, PD1 expression correlated significantly with four co-inhibitory receptors (LAG3, TIM3, TIGIT, VISTA) and one co-stimulatory molecule (CD137). In urothelial carcinoma, PD1 expression significantly correlated with four co-inhibitory (TIGIT, CTLA4, LAG3, VISTA) and four co-stimulatory (OX40, CD27, CD137, HVEM) molecules. In pancreatic adenocarcinoma, only CD28 showed a significant correlation with PD1 expression. No significant correlations with PD1 expression were found in the ovarian cancer cohort. Notably, melanoma and urothelial carcinoma exhibited a dominant co-expression of co-inhibitory molecules with PD1, indicative of exhausted T cells, in contrast to the co-stimulatory molecule dominance in ovarian and pancreatic cancers, suggesting less differentiated T cells. Conclusions: Our findings highlight the potential for diverse combination strategies in immunotherapy, particularly with PD1 blockade, across various cancers.
