Topoisomerase Inhibitors Research Articles

Valemetostat and trastuzumab deruxtecan (T-DXd) in previously treated advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma.

TPS508 Background: Valemetostat tosylate (valemetostat), a novel and selective dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, has demonstrated clinical efficacy and tolerability in multiple hematologic cancers (200 mg orally [PO] once daily [QD]). EZH2 inhibition by valemetostat is expected to upregulate DNA/RNA helicase Schlafen 11 expression and sensitize tumor cells to DNA damaging agents such as topoisomerase I inhibitor antibody–drug conjugates (ADCs). Topoisomerase inhibitors cause DNA strand breaks, which may synergize with valemetostat. HER2 gene amplification or protein expression has been associated with gastric cancer (GC) and GEJ adenocarcinoma. Patients with HER2+ locally advanced or metastatic gastric adenocarcinoma who progress after first line treatment have poor prognosis and limited therapeutic options. T-DXd is approved globally for HER2+ locally advanced or metastatic GC previously treated with a trastuzumab-based regimen. This study evaluates the clinical activity and safety of valemetostat in combination with T-DXd in patients with GC or GEJ adenocarcinoma as part of a Master Protocol trial evaluating valemetostat in combination with ADCs in solid tumors. Methods: This global, phase 1b, multicenter, open-label Master Protocol study (NCT06244485) will enroll ~ 70 patients per sub-protocol in multiple regions, including the US and Japan. The gastric cohort enrolls patients with previously treated advanced or metastatic HER2+ GC or GEJ adenocarcinoma. The dose-escalation (Part 1) will determine the recommended dose for expansion (RDE), combining valemetostat 50–200 mg PO QD with T-DXd 5.4 or 6.4 mg/kg intravenously every 3 weeks. The dose-expansion (Part 2) will assess the efficacy of valemetostat + T-DXd at the RDE. Primary endpoints include safety and tolerability in Part 1 and the objective response rate in Part 2. Secondary endpoints include response duration, progression-free and overall survival, pharmacokinetics, and HER2 expression by immunohistochemistry and in situ hybridization with clinical response. An interim futility analysis will be performed when 20 patients are enrolled with ≥ 6 months of follow-up. Clinical trial information: NCT06244485 .

Genetic mutations and cytotoxic chemotherapy response for advanced solid tumors: A detailed analysis using the C-CAT database in Japan.

130 Background: Chemotherapy regimens are selected based on information about the primary organ or its histological type and are administered based on the results of previous clinical trials. Even now, as cancer genomic research has progressed and precision medicine, which optimizes therapeutic interventions based on tumor genome profiling using next-generation sequencing(NGS), has become standard treatment, cytotoxic anticancer drugs still remain key drugs. We examined the real-world database of genomic and clinical information established by the national central datacenter, the Center for Cancer Genomics and Advanced Therapy (C-CAT) to systematically analyze the effects of mutations across multiple cancers and therapies. Methods: This study delineated the association between genetic mutations and the therapeutic efficacy of cytotoxic chemotherapy in advanced solid tumors in a real-world Japanese clinical context. We incorporated data from 15,474 patients enrolled in the C-CAT database between June 2019 and June 2022. We analyzed the overall response and time to next treatment (TNT) for genetic alterations and five categories of cytotoxic anticancer drugs in gastrointestinal cancers. Results: In the C-CAT data, gastrointestinal cancers were frequently registered, with colorectal cancer being the most common, followed by pancreatic cancer, esophageal/gastric cancer, and biliary tract cancer. For platinum-based drugs, in colorectal cancer, the presence of gene X was associated with not only a higher response rate but also a longer TNT (hazard ratio 0.82, p<0.001). In the case of colorectal cancer and pancreatic cancer with KRAS gene mutations, the ORR was low, and the TNT was also short in the case of pancreatic cancer (hazard ratio 1.33, p<0.001). Interestingly, when BRCA2 genes are mutant, TNT tended to be longer in many organs, suggesting that platinum-based drugs are effective across organs in carcinomas with BRCA2 mutations. Additionally, gene X showed differences in efficacy not only for platinum but also for antimetabolites and topoisomerase inhibitors. Moreover, KRAS mutation was observed in almost all pancreatic cancers and was a treatment-resistant mechanism for all platinum drugs and antimetabolites. Conclusions: This study demonstrated that the effects of cytotoxic anticancer drugs differ depending on genetic mutations. When determining chemotherapy regimens, considering not only the organ but also genetic mutations may enable more efficient drug selection.

Discovery, synthesis, and antibacterial activity of novel myrtucommulone analogs as inhibitors of DNA gyrase and topoisomerase IV.

Drug-resistant bacterial infections have emerged as a new challenge in anti-infective treatment, posing a significant threat to public health. DNA gyrase and topoisomerase IV (Topo IV) are promising targets for designing new antibiotics. Myrtus communis L. has long been used as a traditional herb for antisepsis and disinfection; however, the underlying mechanism of the antibacterial activity remains unclear. In this study, a class of novel myrtucommulone derivatives was synthesized and evaluated for DNA gyrase and Topo IV inhibitions. Analog 27 was the most potent DNA gyrase and Topo IV inhibitor. In bioactivity assays, molecule 27 exhibited a significant antibacterial effect against methicillin-resistant Staphylococcus aureus (MRSA). Additionally, it exhibited rapid bactericidal properties, low toxicity, and low inducing bacterial resistance. It demonstrated synergistic effects with ofloxacin, amikacin, cefepime, and ceftazidime, which make it a potential candidate for antimicrobial application. This work will facilitate the future development of myrtucommulone-based DNA gyrase and Topo IV inhibitors as novel antimicrobials to combat the increasing prevalence of multidrug-resistant bacteria.

Leveraging large-scale PDO-based assays to optimize antibody-drug conjugate efficacy in CRC.

261 Background: Clinical trials are one of the major barriers in contemporary drug development. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies. Using the largest cohort of matched PDOs, longitudinal clinical data, transcriptomic and WES data in CRC, we explore the use of large PDOs collections to characterize ADC efficacy and affinity through systematic mapping of the relationship between target antigen affinity and payload efficacy. Methods: We have assembled a collection of 85 PDOs from colorectal cancer (CRC), generated from primary tumour samples and metastatic biopsies. Patients ranged from 32 to 89 years old and had experienced an average of 1.54 lines of treatment prior to the PDO-generating tissue sampling. Using gene expression levels of well known target antigens such as CEACAM5, ERBB2, MSLN and TROP2 as a proxy for protein concentration, we explore the relationship between the target antigen affinity and the efficacy of a subset of common payloads including topoisomerase and microtubule inhibitors. This allows us to identify the relationship between two of the three main vectors of ADC efficacy in CRC. Results: We show that topoismerase inhibitor and microtubule inhibitor efficacy relates to the RNA expression level of multiple target antigens commonly used in active clinical trials in CRC. These data match the target antigen and payload couples currently under development or approved in the clinic. We are developing a tool to optimize clinical trial design. This approach will allow us to match patients more accurately with the appropriate payload, ensuring a higher likelihood of response. Conclusions: We report that large-scale PDO-based assays can be a useful tool to anticipate clinical readouts. This work suggests that well-characterized PDO collections could also help redefine patient populations, increasing the likelihood of identifying those more likely to respond to a given ADC, and thus improving the success rates of clinical studies for new treatments in CRC.

A phase II open-label study of sacituzumab govitecan in patients with previously treated locally advanced, recurrent, or metastatic cholangiocarcinoma (SIGNA).

TPS651 Background: Cholangiocarcinoma (CCA) is a highly aggressive cancer with limited treatment options. Trop-2, a transmembrane calcium signal transducer, plays a key role in cellular self-renewal, proliferation, and transformation, thereby promoting tumorigenesis. Its overexpression has been associated with disease progression and shorter survival in several epithelial tumors, including CCA. Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of a humanized anti-trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody coupled to SN-38, the active metabolite of the topoisomerase inhibitor, irinotecan. Based on the results from the Phase III ASCENT trial, SG was approved by the FDA for treating relapsed or refractory triple-negative breast cancer and hormone receptor-positive breast cancer, regardless of Trop-2 expression. Given Trop-2's expression in CCA, SG is being investigated as a potential treatment option in this setting. Methods: This Phase II, non-randomized, open-label, single-arm study is being conducted at the University of Kansas Cancer Center and its affiliated sites. Eligibility : Key inclusion criteria include patients with locally advanced, recurrent, or metastatic CCA who have undergone at least one line of prior therapy, have adequate archival tissue for biomarker evaluation or are willing to undergo a biopsy, and have an ECOG performance status of 0-1. Key exclusion criteria include known homozygosity for the UGT1A1*28 allele, which is associated with irinotecan toxicity, and prior treatment with topoisomerase I inhibitors. Treatment Plan : SG is administered at 10 mg/kg intravenously on Days 1 and 8 of every 21-day cycle. Imaging will be performed every 6 weeks. Biopsies will be required both prior to treatment and on-treatment (between Days 15-21 of Cycle 1). Objectives : Primary objective: To determine the anti-tumor activity of SG as measured by the overall response rate (ORR) according to RECIST 1.1. Secondary objectives: To assess treatment safety in participants who have received at least one dose of SG, and to evaluate anti-tumor activity based on progression-free survival (PFS), disease control rate (DCR), and overall survival (OS). Statistical Plan : The sample size (n=22) was calculated using a modified Simon two-stage design, hypothesizing an improvement in ORR to 25%, compared to a baseline value of 8%. In the first stage, 14 patients will be enrolled. If ≤1 participant demonstrates an ORR, the study will be stopped for futility. If ≥2 participants show ORR, an additional 8 patients will be enrolled (total n=22). The study will be deemed successful if ≥4 participants achieve an ORR. This design provides 80.9% power with an 8.5% type I error rate. Stopping rules include halting the trial if the grade 4-5 treatment-related toxicity rate reaches 10%. Enrollment is ongoing. Clinical trial information: NCT06178588 .

The prognostic impact of SLFN11 gene expression in metastatic colorectal cancer (mCRC).

254 Background: SLFN11 was recently identified as a dominant determinant of response to DNA-damaging anticancer agents. Several studies showed SLFN11 expression led to better sensitivity to topoisomerase inhibitors and PARP inhibitors. However, clinical evidence in mCRC has been lacking. Methods: Two independent cohorts (CALGB/SWOG 80405 trial and a real-world patient [Caris CODEai] cohort) were included in this study. Patients were stratified into SLFN11 -high and -low groups based on the median SLFN11 gene expression levels. Survival outcomes were compared between SLFN11 -high and SLFN11 -low in irinotecan-treated and oxaliplatin-treated patients. Median time was estimated using Kaplan-Meier method and Cox models were used for covariate adjustment. Endpoints of interest were progression-free survival (PFS) and overall survival (OS). Results: In the CALGB/SWOG 80405 trial cohort, 433 patients were included (110 treated with FOLFIRI-based chemotherapy and 323 treated with FOLFOX-based chemotherapy). In patients treated with FOLFIRI-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS, 13.4 vs 11.2 months, log-rank p = 0.03, adjusted hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.55-1.39, p = 0.50) and OS (median OS, 39.6 vs 30.3 months, log-rank p = 0.02, adjusted HR = 0.73, 95% CI 0.46-1.16, p = 0.19) compared to SLFN11 -high patients. In patients treated with FOLFOX-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS 11.2 vs 9.8 months, log-rank p = 0.03, adjusted HR = 0.83, 95% CI 0.65-1.05, p = 0.12) and OS (31.1 vs 26.1 months, log-rank p = 0.07, adjusted HR = 0.84, 95% CI 0.65-1.08, p = 0.16) compared to SLFN11 -high patients. No significant interaction was observed between treatment and SLFN11 expression in terms of PFS ( p = 0.69) and OS ( p = 0.44). In the Caris CODEai cohort, a better OS in SLFN11 -low patients than in SLFN11 -high patients was observed in irinotecan-treated patients ( N = 2906) (median OS, 25.5 vs 21.7 months, HR = 0.90, 95% CI 0.82-1.00, p = 0.048). However, no significant difference in OS between SLFN11 -low and SLFN11-high was observed in oxaliplatin-treated patients ( N = 4428) (median OS, 39.5 vs 35.8 months, HR = 0.98, 95% CI 0.90-1.06, p = 0.56). Conclusions: Low SLFN11 expression showed a potential for better prognosis in mCRC patients receiving irinotecan- and oxaliplatin-containing chemotherapies. These findings are not consistently aligned with preclinical data and clinical evidence in other cancer types previously reported. Further investigation is warranted to better understand the biological role and clinical implication of SLFN11 in mCRC.

Quinoline and quinolone carboxamides: A review of anticancer activity with detailed structure-activity relationship analysis.

Quinoline is a highly privileged scaffold with significant pharmacological potential. Introducing a carbonyl group into the quinoline ring generates a quinolone ring, which exhibits promising biological properties. Incorporating a carboxamide linkage at different positions within the quinoline and quinolone frameworks has proven an effective strategy for enhancing pharmacological properties, particularly anticancer potency. Consequently, various scientific communities have explored quinoline and quinolone carboxamides for their anticancer activities, introducing modifications at key positions. This review article aims to compile the anticancer activity of various quinoline and quinolone carboxamide derivatives, accompanied by a detailed structure-activity relationship (SAR) analysis. It also categorizes the data into activities of isolated/fused quinoline and quinolone carboxamide derivatives, which were further subclassified based on the mechanisms of anticancer action. Among the numerous derivatives studied, compounds 8, 19, 31, 34, 40, 68, 108, 116, and 132 have emerged as the most potent anticancer agents, making them strong candidates for further drug design and development. The mechanisms underlying the anticancer activity of these potent compounds have been identified as inhibitors of topoisomerase (8, 19, 31, and 34), protein kinase (40, 108, and 116), human dihydroorotate dehydrogenase (68), and as a cannabinoid receptor 2 agonist (132). We anticipate this review will be valuable to researchers engaged in the structural design and development of quinoline and quinolone carboxamide-based anticancer drugs with high efficacy.

Etoposide as a Key Therapeutic Agent in Lung Cancer: Mechanisms, Efficacy, and Emerging Strategies.

Topoisomerase II inhibitors, particularly etoposide, have long been integral to the treatment of lung cancer, especially small cell lung cancer. This review comprehensively examines the mechanisms of action of etoposide, its clinical efficacy, and its role in current lung cancer treatment regimens. Etoposide exerts its anticancer effects by inducing DNA strand breaks through the inhibition of topoisomerase II, leading to cancer cell apoptosis. Despite their widespread use, challenges such as drug resistance, toxicity, and limited efficacy in non-small cell lung cancer have spurred ongoing research on combination therapies and novel drug formulations. Emerging therapeutic strategies include the integration of etoposide with immunotherapy, targeted therapies, and novel drug delivery systems aimed at enhancing the therapeutic window and overcoming drug resistance. This article aims to inform the development of more effective treatment strategies by providing a critical overview of the clinical applications of etoposide and exploring future directions for lung cancer therapy.

Multifunctional Mycobacterial Topoisomerases with Distinctive Features.

Tuberculosis (TB) continues to be a major cause of death worldwide despite having an effective combinatorial therapeutic regimen and vaccine. Being one of the most successful human pathogens, Mycobacterium tuberculosis retains the ability to adapt to diverse intracellular and extracellular environments encountered by it during infection, persistence, and transmission. Designing and developing new therapeutic strategies to counter the emergence of multidrug-resistant and extensively drug-resistant TB remains a major task. DNA topoisomerases make up a unique class of ubiquitous enzymes that ensure steady-state level supercoiling and solve topological problems occurring during DNA transactions in cells. They continue to be attractive targets for the discovery of novel classes of antibacterials and to develop better molecules from existing drugs by virtue of their reaction mechanism. The limited repertoire of topoisomerases in M. tuberculosis, key differences in their properties compared to topoisomerases from other bacteria, their essentiality for the pathogen's survival, and validation as candidates for drug discovery provide an opportunity to exploit them in drug discovery efforts. The present review provides insights into their organization, structure, function, and regulation to further efforts in targeting them for new inhibitor discovery. First, the structure and biochemical properties of DNA gyrase and Topoisomerase I (TopoI) of mycobacteria are described compared to the well-studied counterparts from other bacteria. Next, we provide an overview of known inhibitors of DNA gyrase and emerging novel bacterial topoisomerase inhibitors (NBTIs). We also provide an update on TopoI-specific compounds, highlighting mycobacteria-specific inhibitors.

Formulation And Evaluation of Betulinic Acid Loaded Transdermal Patches

Many disorders, including cardiovascular diseases, Parkinson's disease, Alzheimer's disease, fungal diseases, depression, anxiety, and Attention Deficit Hyperactivity Disorder (ADHD), skin cancer, female sexual dysfunction, post-menopausal bone loss, and urine incontinence, can now be treated with transdermal delivery systems. A naturally occurring pentacyclic triterpenoid, betulinic acid possesses antiretroviral, antimalarial, and anti-inflammatory qualities. More recently, it has been shown to have anticancer potential through topoisomerase inhibition. The goal of the current study was to create transdermal patches with a controlled release action that included several polymers and an anti-inflammatory medication, such as betulinic acid..The solvent evaporation approach was successfully used to create the betulinic acid transdermal patch. Betulinic acid transdermal patches for transdermal medication administration were assessed. A calibration curve was acquired, a transdermal film was made, and the drug's bioavailability constraints were addressed. Keywords: Controlled DDS, Transdermal DDS, Betulinic acid, Transdermal Patch, solvent evaporation method.

Recent Advances in the Clinical Translation of Small-Cell Lung Cancer Therapeutics.

Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, representing 15% of lung cancer cases globally. SCLC is classified within the range of neuroendocrine pulmonary neoplasms, exhibiting shared morphologic, ultrastructural, immunohistochemical, and molecular genomic features. It is marked by rapid proliferation, a propensity for early metastasis, and an overall poor prognosis. The current conventional therapies involve platinum-etoposide-based chemotherapy in combination with immunotherapy. Nonetheless, the rapid emergence of therapeutic resistance continues to pose substantial difficulties. The genomic profiling of SCLC uncovers significant chromosomal rearrangements along with a considerable mutation burden, typically involving the functional inactivation of the tumor suppressor genes TP53 and RB1. Identifying biomarkers and evaluating new treatments is crucial for enhancing outcomes in patients with SCLC. Targeted therapies such as topoisomerase inhibitors, DLL3 inhibitors, HDAC inhibitors, PARP inhibitors, Chk1 inhibitors, etc., have introduced new therapeutic options for future applications. In this current review, we will attempt to outline the key molecular pathways that play a role in the development and progression of SCLC, together with a comprehensive overview of the most recent advancements in the development of novel targeted treatment strategies, as well as some ongoing clinical trials against SCLC, with the goal of improving patient outcomes.

Design and Synthesis of Topoisomerases-Histone Deacetylase Dual Targeted Quinoline-Bridged Hydroxamates as Anticancer Agents.

The multifactorial nature of cancer requires treatment that involves simultaneous targeting of associated overexpressed proteins and cell signaling pathways, possibly leading to synergistic effects. Herein, we present a systematic study that involves the simultaneous inhibition of human topoisomerases (hTopos) and histone deacetylases (HDACs) by multitargeted quinoline-bridged hydroxamic acid derivatives. These compounds were rationally designed considering pharmacophoric features and catalytic sites of the cross-talk proteins, synthesized, and assessed for their anticancer potential. Our findings revealed that the compound 5c significantly produced anticancer effects in vitro and in vivo by reducing the tumor growth and its size in the A549 cell-induced lung cancer xenograft model through multiple mechanisms, primarily by multi-inhibition of hTopoI/II and HDACs, especially HDAC1 via atypical binding. The present paper discusses detailed mechanistic biological investigations, structure-activity effects supported by computational docking studies, and DMPK studies and provides future scope for lead optimization and modification.

Anti-Mycobacterial Activity of Bacterial Topoisomerase Inhibitors with Dioxygenated Linkers.

Developing new classes of drugs that are active against infections caused by Mycobacterium tuberculosis is a priority for treating and managing this deadly disease. Here, we describe screening a small library of 20 DNA gyrase inhibitors and identifying new lead compounds. Three structurally diverse analogues were identified with minimal inhibitory concentrations of 0.125 μg/mL against both drug-susceptible and drug-resistant strains of M. tuberculosis. These lead compounds also demonstrated antitubercular activity in ex vivo studies using infected THP-1 macrophages with minimal cytotoxicity in THP-1, HeLa, and HepG2 cells (IC50 ≥ 128 μg/mL). The molecular target of the lead compounds was validated through biochemical studies of select analogues with purified M. tuberculosis gyrase and the generation of resistant mutants. The lead compounds were assessed in combination with bedaquiline and pretomanid to determine the clinical potential, and the select lead (158) demonstrated in vivo efficacy in an acute model of TB infection in mice, reducing the lung bacterial burden by approximately 3 log10 versus untreated control mice. The advancement of DNA gyrase inhibitors expands the field of innovative therapies for tuberculosis and may offer an alternative to fluoroquinolones in future therapeutic regimens.

Semisynthesis of Glycosmis pentaphylla Alkaloid Derivatives: Pyranoacridone-Hydroxamic Acid Cytotoxic Conjugates with HDAC and Topoisomerase II α Dual Inhibitory Activity.

Inspired by our previous efforts in the semisynthetic modification of naturally occurring pyranoacridones, we report the targeted design and semisynthesis of dual inhibitors of HDAC and topoisomerase II α (Topo II α) derived from Glycosmis pentaphylla des-N-methylacronycine (1) and noracronycine (8) pyranoacridone alkaloids. Designed from the clinically approved SAHA, the cytotoxic pyranoacridone nuclei from the alkaloids served as the capping group, while a hydroxamic acid moiety functioned as the zinc-binding group. Out of 16 compounds evaluated in an in vitro cytotoxicity assay, KT32 (10c) with noracronycine (8) as the capping group and five-carbon linker hydroxamic acid side chains showed good cytotoxic activity with IC50 values of 1.0, 1.5, and 0.3 μM on MCF-7, CALU-3, and SCC-25 cell lines, respectively. KT32 (10c) showed potent HDAC inhibitory activity and partial Topo II α inhibitory activity in both enzyme assays. The SAR results strongly aligned with the predicted binding affinities from the molecular docking study. KT32 (10c) was further explored for a preliminary mechanistic understanding of SCC-25 cell lines. Flow cytometry analysis suggests that KT32 (10c) induces cell death through apoptosis, as evidenced by the substantial increase in the population of late apoptotic cells.

Targeting Metabolic and Epigenetic Vulnerabilities in Glioblastoma with SN-38 and Rabusertib Combination Therapy.

Glioblastoma (GBM), the most prevalent primary malignant brain tumor, remains challenging to treat due to extensive inter- and intra-tumor heterogeneity. This variability demands combination treatments to improve therapeutic outcomes. A significant obstacle in treating GBM is the expression of O6-methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces the efficacy of the standard alkylating agent, temozolomide, in about 50% of patients. This underscores the need for novel, more targeted therapies. Our study investigates the metabolic-epigenetic impact of combining SN-38, a novel topoisomerase inhibitor inducing DNA double-strand breaks, with rabusertib, a checkpoint kinase 1 inhibitor. We identified this synergistic combination through high-throughput drug screening across a panel of GBM cell lines using a cancer drug library combined with SN-38. A secondary metabolic screening with the PEDS algorithm demonstrated a synergistic modulation of purine, one-carbon, and redox metabolism. Furthermore, the combined treatment led to the significant depletion of epigenetically relevant metabolites such as 5-methyl-cytosine, acetyl-lysine, and trimethyl-lysine. Reduced intermediates of the glutathione cycle indicated increased cellular stress following combinatorial treatment. Overall, the combination of SN-38 and rabusertib synergistically disrupts metabolites associated with epigenetic adaptations, leading to cytotoxicity independent of O6-methylguanine-DNA methyltransferase status, thereby underpinning this combination as a promising candidate for combinatorial therapy in GBM.

Coralyne Targets the Catalytic Domain of MMP9: An In Silico and In Vitro Investigation.

Coralyne (COR) is a protoberberine-like isoquinoline alkaloid, and it is known for double-stranded (ds) DNA intercalation and topoisomerase inhibition. It can also sensitize cancer cells through various mechanisms. COR reduces the proliferation and migration of breast cancer cells by inhibiting the expression and activity of matrix metalloproteinase 9 (MMP9). However, the mechanism involved in the inhibitory activity of COR on MMP9 is not known. In the present study, in silico docking studies showed that COR binds to the active site of MMP9 catalytic domain (MMP9-CD) with considerable affinity. The binding affinity of COR to the MMP9-CD, estimated by three different web servers: CB Dock, Seam Dock, and PyRx, was found to be either -7.4 or -7.5 kcal/mol. Another web server that is routinely used for docking studies, Docking Server, has predicted a binding affinity of -5.9 kcal/mol. All four docking servers predicted the same binding site for COR within the MMP9-CD. Corroborating our docking results, molecular dynamic simulation studies have also shown that COR interacts with the same key active site amino acid residues of the MMP9-CD that are essential for its proteolytic function. Molecular mechanics with generalized born and surface area (MMGBSA) calculations using Schrodinger's prime module have shown that the binding free energy with which COR binds to MMP9 is -50 kcal/mol. It inhibited activity of recombinant human MMP9 activity and induced significant cytotoxicity and reduced the proliferation of MDA-MB 468 cells. Overall, our in silico and in vitro experiments show that COR potentially inhibits the activity of MMP9 by directly binding to the active site of its catalytic domain and possibly inhibits proliferation of MDA-MB 468 cells.

Noncanonical inhibition of topoisomerase II alpha by oxidative stress metabolites

Noncanonical inhibition of topoisomerase II alpha by oxidative stress metabolites

Enhanced antitumor immunity in breast cancer: Synergistic effects of ADAM10/ADAM17 inhibition, metabolic modulation, and camptothecin-loaded selenium nanoparticles.

In this study, we investigate the impact of a multi-targeted therapeutic approach that includes camptothecin (CPT), a potent chemotherapeutic topoisomerase inhibitor; metformin (Met), a metabolic modulator with emerging anti-tumor effects; and GW280264X, an inhibitor of ADAM 10/ADAM 17 enzymes, which are associated with tumor invasion and immune response. The study aims to assess the combined effects of these agents in enhancing CD8+ T cell-mediated anti-tumor immunity and suppressing cancer cell growth in triple-negative breast cancer (TNBC) models, both in vitro and in vivo. Cell viability was performed on the 4T1 human TNBC cell line. Furthermore, we examined c-MYC protein expression by western blot, TOX and NR4A expression by Real-time PCR, and the number of CD8+ CD28+ T cells by immunofluorescence assay to demonstrate the anticancer effects of combined of CPT, Met and GW280264X in BC growth, exhaustion and senescence of T cells. Regarding cell viability, HA-Se@CPT+Met and HA-Se@CPT+Met+GW280264X treatments decreased 4T1 cell growth (p<0.001). Combination therapy of Met, HA-Se@CPT, and GW280264X significantly reduced tumor volume and weight in vivo. This treatment also increased the number of CD8+ CD28+ T cells in the tumor microenvironment (TME) of BC (p<0.0001) and decreased the expression of TOX and NR4A (p<0.0001, p<0.01). Furthermore, decreased expression of c-MYC as an oncogene protein was seen in the single and combined treatment by HA-Se@CPT and GW280264X (p<0.05). These findings suggest that of HA-Se@CPT, Met, and GW280264X may inhibit tumor progression in BC by improving the function and infiltration of CD8+ T cells. Their effect is more pronounced when used in combination.

A prospective observational study on iv compatibility, dose adjustment and ADR of chemotherapy drugs in oncology department at tertiary care hospital

Background: Cancer is the second leading cause of death worldwide. Chemotherapy is a standard modality of cancer treatment that uses chemical agents or drugs to destroy cancer cells in the cell cycles or use chemicals or drugs to inhibit cancerous cells growth and spread. The objective of this study was to assess the IV compatibility of chemotherapy drug in different solution, assess the frequency of ADR, classify ADR according to the class of drug and dose adjustment. Methods: In this study, cancer patients of either gender (aged 21-90) admitted on the oncology department of Bangalore Baptist Hospital were included in the study. Assessment of IV compatibility was done based on the prescription pattern, dose adjustment was done on the basis of body weight, BSA and hepatic and renal parameters. Adverse reactions reported by the patients, assessed by the doctors and nurses and changes in the laboratory parameters were analysed for the assessment of ADR. Results: A total of 43 patients met the inclusion criteria; among which 44% were male and 56% were female. The mean age of the study was 57.49. Breast cancer, stomach cancer and lung cancer were more prevalent. In the study 24 chemotherapy drugs were used among them 20 drugs were compatible in 0.9% normal saline and 4 drugs were compatible in 5% dextrose. Dose adjustment were done for 4 drugs which were Carboplatin, Paclitaxel, Trastuzumab and Ifosfamide. The average dose adjusted for Carboplatin, Paclitaxel, Trastuzumab and Ifosfamide were -0.46±3.3, 0.5±10.6, -10±0 and -50±0 respectively. Total of 25 adverse drug reaction were seen where vomiting, gastritis and anemia were more frequently seen. Alkylating agents showed more number of ADRs. Conclusions: From the study, it can be concluded that most of the chemotherapy drugs were compatible either in 5% dextrose or 0.9% normal saline. Dose adjustments were done on the basis of body weight and BSA. Alkylating agents showed ADR most frequently and least frequent was topoisomerase inhibitor. Vomiting was the most reported ADR.

Phosphine Oxide Indenoquinoline Derivatives: Synthesis and Biological Evaluation as Topoisomerase I Inhibitors and Antiproliferative Agents.

The synthesis of phosphorous indenoquinolines and their biological evaluation as topoisomerase 1 (TOP1) inhibitors and antiproliferative agents were performed. First, the preparation of new hybrid 5H-indeno[2,1-c]quinolines with a phosphine oxide group was performed by a two-step Povarov-type [4+2]-cycloaddition reaction between the corresponding phosphorated aldimines with indene in the presence of BF3·Et2O. Subsequent oxidation of the methylene present in the structure resulted in the corresponding indeno[2,1-c]quinolin-7-one phosphine oxides 10. The synthesized derivatives were evaluated as TOP1 inhibitors showing higher inhibition values than CPT at prolonged incubation times (5 min). Inhibition of TOP1 was even observed after 30 min of incubation. The cytotoxic activities of these compounds were also studied against different cancer cell lines and a non-cancerous cell line. While some compounds showed cytotoxicity against some cancerous cells, none of the compounds showed any cytotoxicity against the non-cancerous cell line, MRC-5, in contrast to CPT, which exhibits high toxicity against this cell line. These results represent a very interesting advance since the heterocyclic phosphine oxide derivatives have important properties as TOP1 inhibitors and show an interesting cytotoxicity against different cell lines.