Topoisomerase Research Articles

Therapeutic co-assemblies for synergistic NSCLC treatment through dual topoisomerase I and tubulin inhibitors

Camptothecin (CPT) and podophyllotoxin (PPT) function as topoisomerase (TOP) I and tubulin inhibitors, respectively, with potent anticancer effects in a variety of cancers. Despite its promise, the clinical applicability of the combination of CPT and PPT faces challenges, including potential side effect and limited therapeutic efficacy. In this study, we designed co-assembly nanomedicines with the different weight (w/w) ratios of amphiphilic Evans blue conjugated CPT prodrug (EB-ss-CPT) and PPT molecules, denoted as ECT Nano. The co-assembly of EB-ss-CPT and PPT without other excipients has nearly 100% drug loading efficiency and high drug loading content of PPT of up to 74.29 ± 0.90 wt%. Notably, the ECT Nano (1:2) equipped with the ability to inhibit TOP I activity and tubulin polymerization, which provided a highly efficient strategy to improve synergistic efficacy and decrease side toxicity in non-small cell lung cancer mouse model. This work represents a step forward to the development of practical applications for dual TOP I and tubulin inhibitors and especially hopeful to the rational design of combination nanomedicine for therapeutic purposes.

Prognostic prediction for HER2-low breast cancer patients using a novel machine learning model

BackgroundsTo develop a machine learning (ML) model for predicting the prognosis of breast cancer (BC) patients with low human epidermal growth factor receptor 2 (HER2) expression, and to investigate the association between clinicopathological characteristics and outcomes in HER2-low BC (HLBC) patients.MethodsA retrospective analysis was conducted on data from 998 female HLBC patients treated at the Breast Center of the Fourth Hospital of Hebei Medical University (Hebei, China) between January 1, 2017, and December 31, 2020. To address class imbalance, the synthetic minority over-sampling technique was applied. Feature selection was performed using the least absolute shrinkage and selection operator, followed by construction of the prediction model using the random forest algorithm. Model performance, including specificity and accuracy, was assessed using the receiver operating characteristic (ROC) curve and confusion matrix, comparing it against other ML models. Additionally, the log-rank test was employed to examine the relationship between selected features and patient outcomes in HLBC.ResultsThe random survival forest model demonstrated superior accuracy and specificity in predicting survival outcomes for HLBC patients. Compared with other ML models, it achieved more precise predictions of Disease-Free Survival (DFS) at 1, 2, and 3 years, with the area under the ROC curve (AUC) in the test and training cohorts measured at 0.726 and 0.819, 0.712 and 0.776, and 0.685 and 0.774, respectively. The analysis further identified a strong correlation between poor prognosis in HLBC patients and factors such as axillary lymph node dissection, family history, elevated topoisomerase (TOPO)-2 expression, advanced clinical stage, negative progesterone receptor status, P53 mutation, and increased Ki67 expression, observed across both cohorts.ConclusionsA novel ML model was developed for accurate prognosis prediction in HLBC patients, offering valuable insights into prognostic risk factors. This model equips clinicians with enhanced data to guide treatment decisions, ultimately contributing to improved patient outcomes.

Structural basis of chiral wrap and T-segment capture by Escherichia coli DNA gyrase

Type II topoisomerase DNA gyrase transduces the energy of ATP hydrolysis into the negative supercoiling of DNA. The postulated catalytic mechanism involves stabilization of a chiral DNA loop followed by the passage of the T-segment through the temporarily cleaved G-segment resulting in sign inversion. The molecular basis for this is poorly understood as the chiral loop has never been directly observed. We have obtained high-resolution cryoEM structures of Escherichia coli gyrase with chirally wrapped 217 bp DNA with and without the fluoroquinolone moxifloxacin (MFX). Each structure constrains a positively supercoiled figure-of-eight DNA loop stabilized by a GyrA β-pinwheel domain which has the structure of a flat disc. By comparing the catalytic site of the native drug-free and MFX-bound gyrase structures both of which contain a single metal ion, we demonstrate that the enzyme is observed in a native precatalytic state. Our data imply that T-segment trapping is not dependent on the dimerization of the ATPase domains which appears to only be possible after strand passage has taken place.

Antitumor Cream: Transdermal Hydrogel Containing Liposome-Encapsulated Ruthenium Complex for Infrared-Controlled Multimodal Synergistic Therapy.

A transdermal drug delivery cream, which is non-invasive and painless, containing a liposome-encapsulated Ru(II) complex (LipoRu) is created for the treatment of skin cancer. This formulation capitalizes on the synergistic antitumor effects of two-photon excited photodynamic therapy (PDT), photothermal therapy (PTT), and chemotherapy. LipoRu exhibits effective tumor accumulation, efficient cellular uptake, pH-sensitive and infrared-accelerated release, and dual localization to the nucleus and mitochondria. The released Ru(II) complexes within cells exert multiple antitumor mechanisms, such as DNA topoisomerase and RNA polymerase inhibition, Type I and II PDT, PTT, DNA photodamage, and apoptosis and ferroptosis induction. The biodistribution and therapeutic efficacy of LipoRu in vivo are systematically compared via three distinct administration routes: intratumoral injection, intravenous injection, and transdermal delivery through topical cream application. The positive therapeutic effects of the LipoRu cream fabricated here in subcutaneous tumor-bearing mice offer optimistic potential for the painless and non-invasive treatment of both early-stage and advanced skin cancers, as well as superficially located solid tumors.

EXTH-14. IRREVERSIBLE TARGETING OF THE C-MYC/TOPOISOMERASE I AXIS IN GLIOBLASTOMA: DUAL INHIBITION USING A NOVEL INDENOISOQUINOLINE INHIBITOR

Abstract Glioblastoma–the most common primary CNS malignancy–is notorious for its cellular and molecular complexity and uniform fatality. Overexpression of the c-MYC and TOPOISOMERASE 1 (TOP1) oncogenes is implicated in more than 50% of human cancers. They are involved in the pathogenesis of glioblastomas with overexpression correlating with decreased overall median survival in glioblastoma patients. LMP744 is a non-camptothecin indenoisoquinoline small molecule inhibitor designed to target the C-MYC/TOP1 axis. The compound is inherently stable, has high brain penetrance, and irreversibly binds to its target providing several advantages over the camptothecin class of drugs. Human glioblastoma cells treated with LMP744 show a dose-dependent decrease in viability with LD50 ranging between 50 and 100 nM compared to 100-200µM following treatment with temozolomide in the same cell lines. Treatment results in a pro-apoptotic effect in exposed cells as well as S-phase arrest. Protein arrays and confirmatory western blots demonstrate increased CHK2 and decreased p53 and GSK-a/ß in treated cells. Orthotopic xenotransplantation via stereotactic injection of human glioblastoma cells (7×105 cells/4 µL) in nude mice showed exquisite sensitivity to LMP744 without adverse events. Administration of 20 mg/kg of LMP744 via tail vein injection resulted in total eradication of tumor signal on bioluminescent imaging. These preliminary findings suggest that LMP744–and perhaps the class of non-camptothecin indenoisoquinolones–is a promising novel candidate for glioblastoma pharmacotherapy.

DDEL-03. INTRANASAL DELIVERY OF PDGFRA-TARGETED NANOTHERAPEUTICS FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMA

Abstract Pediatric high-grade glioma (pHGG) is the most common cause of cancer-related death in children, of which the most malignant and devastating tumors include diffuse midline glioma (DMG). Its anatomical location in the brainstem, infiltrative nature, and blood-brain barrier (BBB) limit surgical resection and the distribution of systemically administered drugs. Intranasal delivery (IND) is a noninvasive method that bypasses the BBB, by leveraging the unique anatomic connections of the olfactory and trigeminal nerve pathways with the nasal cavity. We previously demonstrated the efficacy of IND of nanoliposomal (LS) formulation of the active metabolite of the DNA topoisomerase I inhibitor, irinotecan, LS-SN-38, in orthotopic human brainstem xenograft models. The specificity of liposomes can be enhanced by using immunoliposome (iLS) formulation, which are coated with antibodies specific to the tumor cells leading to targeted drug delivery and reduced toxicity to normal cells. Platelet-derived growth factor receptor alpha (PDGFRA) plays a role in DMG oncogenesis and is expressed in as much as 70% of DMG by immunohistochemistry. In this study, we evaluated the effect of anti-PDGFRA monoclonal antibody-conjugated immunoliposome encapsulated SN-38 (PDGFRA-iLS-SN-38) in pHGG cell lines. PDGFRA signals were assessed in pHGG cells using western blotting. Cells were treated with rhodamine (Rho)-labeled PDGFRA-iLS and cellular uptake was confirmed with a fluorescent microscope. PDGFRA-iLS-SN38 had the additive effect on the LS-SN-38 in DIPG007 cells (PDGFRA positive), but not in SF8628 cells (PDGFRA negative) in vitro. We treated mice bearing human DMG xenografts with IND of PDGFRA-iLS-SN38. Tumor growth and response to therapy are quantitatively measured by bioluminescence imaging, and efficacy is assessed by survival analysis. Results of survival analysis will be reported at the meeting. PDGFRA-targeted nanotherapeutics represented a specific effect on glioma cells expressing PDGFRA, providing a promising therapeutic approach for targeting pHGG.

Identification of Crucial Cancer Stem Cell Genes Linked to Immune Cell Infiltration and Survival in Hepatocellular Carcinoma.

Hepatocellular carcinoma is characterized by high recurrence rates and poor prognosis. Cancer stem cells contribute to tumor heterogeneity, treatment resistance, and recurrence. This study aims to identify key genes associated with stemness and immune cell infiltration in HCC. We analyzed RNA sequencing data from The Cancer Genome Atlas to calculate mRNA expression-based stemness index in HCC. A weighted gene co-expression network analysis was performed to identify stemness-related gene modules. A single-sample gene set enrichment analysis was used to evaluate immune cell infiltration. Key genes were validated using RT-qPCR. The mRNAsi was significantly higher in HCC tissues compared to adjacent normal tissues and correlated with poor overall survival. WGCNA and subsequent analyses identified 10 key genes, including minichromosome maintenance complex component 2, cell division cycle 6, forkhead box M1, NIMA-related kinase 2, Holliday junction recognition protein, DNA topoisomerase II alpha, denticleless E3 ubiquitin protein ligase homolog, maternal embryonic leucine zipper kinase, protein regulator of cytokinesis 1, and kinesin family member C1, associated with stemness and low immune cell infiltration. These genes were significantly upregulated in HCC tissues. A functional enrichment analysis revealed their involvement in cell cycle regulation. This study identified 10 key genes related to stemness and immune cell infiltration in HCC. These genes, primarily involved in cell cycle regulation, may serve as potential targets for developing more effective treatments to reduce HCC recurrence and improve patient outcomes.

Copper(II) aromatic heterocyclic complexes of Gatifloxacin with multi-targeting capabilities for antibacterial therapy and combating antibiotic resistance

In recent years, the pace of novel antibiotic development has been relatively slow, intensifying the urgency of the antibiotic resistance issue. Consequently, scientists have turned their attention to enhancing antibiotic activity by coordinating antibiotics with metal elements. This study designs and synthesizes three novel antibacterial copper complexes based on Gatifloxacin. These complexes exhibit potent antibacterial activity, notably Cu-1, with a minimum inhibitory concentration (MIC) of only 0.063 μg/mL against Staphylococcus aureus (S.aureus), demonstrating potent bacteriostatic capabilities. Further investigations unveil the antibacterial mechanisms of complex Cu-1, revealing its ability not only to suppress the activities of DNA gyrase and topoisomerases IV, but also to effectively inhibit biofilm formation and disrupt the integrity of cell membrane. This multi-targeting action contributes to mitigating the risk of bacterial resistance emergence. Additionally, synergy between Cu-1 and conventional antibiotics is confirmed through checkerboard assays, offering novel strategies for antibacterial therapy. In vivo experiments using a murine model of S.aureus infection demonstrate the significant antibacterial efficacy of Cu-1, providing robust support for its potential in treating S.aureus infections. This study demonstrates that the coordination complexes formed by copper, Gatifloxacin and suitable aromatic heterocyclic ligands exhibit multi-targeting characteristics against bacteria, offering a new direction for combating antibiotic resistance in antibacterial therapy.

Computational Screening of Novel Nitroimidazole Candidates: Targeting Key Enzymes of Oral Anaerobes for Anti-Parasitic Potential.

The study focuses on evaluating the parasitic potential of novel metronidazole analogs using computational methods. Specifically, it aims to target key enzymes of oral anaerobes, including UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA) of Fusobacterium nucleatum and DNA topoisomerase (Topo) of Prevotella intermedia. The objective is to assess the pharmacokinetic and toxicity properties of 368 novel nitroimidazole candidates through virtual screening. Additionally, the study aims to determine the binding affinity of the most promising candidates with the target proteins through molecular docking analyses. A combinatorial library of nitroimidazole candidates was constructed, and virtual screening was performed. Molecular docking analyses were conducted to evaluate the binding affinity of selected compounds with MurA and Topo. Further investigation involved molecular dynamic simulation to assess the stability of the compounds within the active sites of MurA and Topo. All selected compounds exhibited activity against both MurA and Topo. Among them, Mnz11, Mnz12, and Mnz15 demonstrated the lowest binding free energies and IC50 values. Molecular dynamic simulation indicated that these three compounds remained stable within the active sites of MurA and Topo, with RMSD values consistently below 2Å. Additionally, the antibacterial potential of the most potent compound, Mnz15, was evaluated against a series of oral microbes. The study concludes that the newly identified nitroimidazole candidates show promise as anti-parasitic agents, based on their activity against key enzymes of oral anaerobes and their pharmacokinetic properties evaluated through computational methods.

Design, synthesis, molecular docking, and antibacterial activity of novel amide-linked tetrahydrobenzothienopyrimidinone derivatives as potential DNA gyrase and topoisomerase IV inhibitors

Design, synthesis, molecular docking, and antibacterial activity of novel amide-linked tetrahydrobenzothienopyrimidinone derivatives as potential DNA gyrase and topoisomerase IV inhibitors

Systematic analysis of natural topoisomerase I inhibitors from Forsythiae Fructus by ultrafiltration-UPLC-ESI-MS/MS, pharmacophore modelling, and molecular dynamics simulation

This study conducted a systematic analysis to explore natural DNA topoisomerase I (topo I) inhibitors from Forsythiae Fructus (FF). Crude extract of FF exhibited notable toxic and anti-proliferative effects on A549 cells. A total of 36 components were identified using bioaffinity ultrafiltration UPLC-ESI-MS/MS. Pinoresinol, 1,8-dihydrox­yanthraquinone, quercetin, and lariciresinol were screened as topo I inhibitors. Their ESI fragmentation patterns were analysed. An obvious repair effect on damaged DNA strands was observed by topo I inhibitory binding assay. Moreover, a common feature-based pharmacophore model was constructed and another 7 topo I inhibitors were screened. Molecular docking indicated that hydrogen bond, π-anion, and π-alkyl interaction were major interactions. Molecular dynamics simulation revealed important residues determining the binding of amentoflavone, forsythoside B and topo I. The results improved current understanding of natural topo I inhibitors from FF. Moreover, the combination of multi-disciplinary approaches provided a new tool to investigate natural antitumor products.

Pharmacological Interactions of Jadomycin B with Topoisomerase Poisons in MDA-MB-231 Human Breast Cancer Cells.

Jadomycin B, a natural product isolated from Streptomyces venezuelae, exerts an anti-cancer effect on human triple negative breast cancer cells in vitro and has anti-tumoral effects in vivo in animal models of breast cancer. One proposed mechanism for this anti-cancer effect is through interaction with topoisomerase 2 (TOP2). Based on the previously described interactions between jadomycin B and TOP2 we hypothesized that jadomycin B will act additively with TOP2 poisons and produce a similar functional outcome in eliciting cell cycle arrest. Combined treatments of jadomycin B and the TOP2 poisons doxorubicin or mitoxantrone produced moderately synergistic to additive cytotoxicity (combination index values ranging from 0.72-0.94) in MDA-MB-231 cells. In comparison, combined mitoxantrone and doxorubicin produced additive cytotoxicity (combination index values 0.96-1.11). Jadomycin B combined with the proteosome inhibitor MG132 had additive cytotoxicity (combination index values 0.76-1.18). In contrast, mitoxantrone or doxorubicin cytotoxicity was antagonized by MG132 (combination index values 1.21-2.31). Jadomycin B treatment arrested cells in S-phase (P = 0.0024) as opposed to mitoxantrone which caused G2/M-phase arrest (P < 0.0001). In conclusion, jadomycin B interacts differently than known TOP2 poisons in combination, supporting a novel pharmacological mechanism(s) of action for jadomycin B cytotoxicity.

Novel 1,8-Naphthalimide Derivatives Inhibit Growth and Induce Apoptosis in Human Glioblastoma.

Given the rapid advancement of functional 1,8-Naphthalimide derivatives in anticancer research, we synthesized these two novel naphthalimide derivatives with diverse substituents and investigated the effect on glioblastoma multiforme (GBM) cells. Cytotoxicity, apoptosis, cell cycle, topoisomerase II and Western blotting assays were evaluated for these compounds against GBM in vitro. A human GBM xenograft mouse model established by subcutaneously injecting U87-MG cells and the treatment responses were assessed. Both compounds 3 and 4 exhibited significant antiproliferative activities, inducing apoptosis and cell death. Only compound 3 notably induced G2/M phase cell cycle arrest in the U87-MG GBM cells. Both compounds inhibited DNA topoisomerase II activity, resulting in DNA damage. The in vivo antiproliferative potential of compound 3 was further validated in a U87-MG GBM xenograft mouse model, without any discernible loss of body weight or kidney toxicity noted. This study presents novel findings demonstrating that 1,8-Naphthalimide derivatives exhibited significant GBM cell suppression in vitro and in vivo without causing adverse effects on body weight or kidney function. Further experiments, including investigations into mechanisms and pathways, as well as preclinical studies on the pharmacokinetics and pharmacodynamics, may be instrumental to the development of a new anti-GBM compound.

Epigenetic control of Topoisomerase 1 activity presents a cancer vulnerability.

DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from aberrant TOP1 activity remains unknown. Here, we identify chromatin context as an essential means to coordinate TOP1cc resolution. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. By visualizing transcription-induced topological stress in single cells, we find that macroH2A1.1 facilitates PAR-dependent recruitment of the TOP1cc repair effector XRCC1 to protect from ssDNA damage. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors. We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.

In silico Study of Novel Tryptanthrin-Based Topoisomerase Inhibitors

Background: Over the past ten years, a remarkable number of changes have occurred in the field of cancer drug research. Most anticancer drugs from the first generation work by breaking down DNA, preventing its production, interfering with cell division processes, or attaching to microtubules. The potential use of tryptanthrin as well as its analogues is well documented for anticancer properties. Objective: To design a novel hybrid of tryptanthrin analogs with expected anticancer activity. Method: By changing the C-6 carbonyl position of the tryptanthrin molecule, a set of 72 derivatives of substituted-6-benzylidine-6H-indolo[2,1-b] quinazoline-12-one was developed. These ligands were screened in silico using Schrodinger Glide extra precision docking against DNA topoisomerase using doxorubicin and teniposide as references to identify their potential anticancer properties. Further, these ligands were subjected to an in silico ADMET study to identify their drug likeliness. Results: Combined results of molecular docking and in silico ADMET study suggest that out of the total 72 ligands, 6 ligands RC 51, RC 29, RC 42, RC 3, RC 54, and RC 63 were showing very better binding affinity than the natural ligand adenylyl-imidodiphosphate and the two standard reference drugs- doxorubicin and teniposide. Conclusion: Our computational approach was successful in identifying ligands that are potentially potent topoisomerase inhibitors. These can be tested further using in vitro and in vivo analysis.

Synthesis of New Pyrazolo[3,4-d]pyrimidine Derivatives: NMR Spectroscopic Characterization, X-Ray, Hirshfeld Surface Analysis, DFT, Molecular Docking, and Antiproliferative Activity Investigations.

Four new pyrazolo[3,4-d]pyrimidines (P1-P4) were successfully synthesized in good relative yields by reacting 3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol with various alkylating agents (methyl iodide, propargyl bromide, and phenacyl bromide) at room temperature in DMF solvent, employing liquid-solid phase transfer catalysis. The P1-P4 structures were elucidated using NMR spectroscopy and X-ray diffraction. Intermolecular interactions in P1-P4 were analyzed via Hirshfeld surface analysis and 2D fingerprint plots. Geometrical parameters were accurately modeled by DFT calculations using the B3LYP hybrid functional combined with a 6-311++G(d,p) basis set. The antiproliferative activity of P1-P4 towards colorectal carcinoma (HCT 116), human hepatocellular carcinoma (HepG2), and human breast cancer (MCF-7) cell lines, along with one normal cell line (WI38) was investigated using the MTT assay and sunitinib as a reference. Compounds P1 and P2 exhibited antiproliferative activities comparable to the reference drug towards all tested cells, with an IC50 range of 22.7-40.75 µM. Both compounds also showed high selectivity indices and minimal cytotoxic effects on the normal cell line. Molecular docking revealed that the significant antiproliferative activity may attributed to the number and type of intermolecular hydrogen bonding established between pyrazolo[3,4-d]pyrimidines and DNA topoisomerase, a common target for various anticancer agents.

Enhancing antibacterial efficacy through macrocyclic host complexation of fluoroquinolone antibiotics for overcoming resistance

The use of supramolecular assemblies in pharmaceuticals has garnered significant interest. Recent studies have shown that the activities of antibacterial agents can be enhanced through complexation with cyclic oligomers and metal ions. Notably, these complexes sometimes possess greater therapeutic properties than the parent drugs. To develop microbiologically potent supramolecular drugs, the complexation of macrocyclic hosts with fluoroquinolone (FQ) antibiotics was investigated. FQs are a successful family of antibiotics that target the bacterial enzymes DNA gyrase and DNA topoisomerase IV, leading to bacterial cell death through the inhibition of DNA synthesis. However, antibiotic resistance resulting from the repeated use of FQs over time has limited their effectiveness against resistant pathogens. To overcome this issue, the encapsulation of FQs in polyphenolic macrocycles was investigated. This study highlights resorcinarene, a polyphenolic host with antibacterial properties, and its ability to chemically interact with FQs. The inclusion complexation process was analyzed using NMR and FTIR techniques. The binding constants determined by 1H-NMR titration revealed that levofloxacin forms more stable complexes with resorcinarene than with β-cyclodextrin, which aligned with MD simulations. Assessment of the geometric characteristics of the inclusion complexes using 2D NMR analysis confirmed that different moieties of various FQs can fit into a single host cavity and improve activity against gram-negative bacteria. Overall, these findings suggest that encapsulation in polyphenolic macrocycles is a promising strategy for utilizing FQs against antibiotic-resistant bacteria.

Transcriptome analysis in C. elegans early embryos upon depletion of the Topoisomerase 2/condensin II axis.

In C. elegans , the chromosome compaction factors topoisomerase 2 (TOP-2) and condensin II have been shown to globally repress transcription in multiple contexts. Our group has previously reported that TOP-2 and condensin II repress transcription in the C. elegans germline during larval starvation, oocyte maturation, and in germline progenitor cells of the early embryo. Here, we assess the transcriptome of early embryos treated with RNAi against TOP-2 and the condensin II subunit CAPG-2. We found 144 upregulated and 172 downregulated genes. Further analysis showed that the upregulated genes are mostly somatic, with a host of neuronal cells present in our tissue enrichment analysis.

Emerging Role of Natural Topoisomerase Inhibitors as Anticancer agents

Abstract: Topoisomerases I and II are the functionally two forms of DNA topoisomerase. In anticancer research, novel anticancer chemotherapeutical capable of blocking topoisomerase enzymes have been discovered. Most commonly, topoisomerase causes replication fork arrest and doublestrand breaks, and this is how a clinically successful topoisomerase-targeting anticancer medicines work. Unfortunately, this novel mechanism of action has been linked to the development of secondary malignancies as well as cardiotoxicity. The specific binding locations and mechanisms of topoisomerase poisons have been identified by studying the structures of topoisomerase-drug-DNA ternary complexes. Recent breakthroughs in science have revealed that isoform-specific human topoisomerase II poison could be created as safer anticancer drug molecules. It may also be able to develop catalytic inhibitors of topoisomerases by focusing on their inactive conformations. In addition to this, the discovery of new bacterial topoisomerase inhibitor molecules and regulatory proteins could lead to the discovery of new human topoisomerase inhibitors. As a result, biologists, organic chemists, and medicinal chemists worldwide have been identifying, designing, synthesizing, and testing a variety of novel topoisomerase-targeting bioactive compounds. This review focused on topoisomerase inhibitors, their mechanisms of action, and different types of topoisomerase inhibitors that have been developed during the last ten years.

Myeloid sarcoma mimicking as recurrent squamous cell carcinoma: What is the etiology?

Abstract Introduction/Objective Myeloid sarcoma is an extramedullary malignancy of primitive myeloid cells and can occur during, preceding, or as a relapse of acute myeloid leukemia that occurs mostly in the soft tissue and skin. Methods/Case Report A 77-year-old white male with a history of oral squamous cell carcinoma status post resection (18 months ago) followed by radiation and chemotherapy (15 months prior), presented to the ear nose and throat clinic with increasing weakness and dizziness. He received two doses of Cisplatin and was currently on Pembrolizumab. On examination, there were two lesions in the oral cavity, one on the right gingivobuccal sulcus and a second on the left posterior mandibular ridge, suspicious for squamous cell carcinoma recurrence. Interestingly, the biopsy did not show evidence of recurrent squamous cell carcinoma but showed sheets of blasts that were positive for MPO, CD117, CD43, and CD68, consistent with myeloid sarcoma. Subsequent peripheral blood and bone marrow examinations showed acute myeloid leukemia. Results (if a Case Study enter NA) NA Conclusion Myeloid neoplasms post-cytotoxic therapy (MN-pCT) occur after radiation, alkylating agents, DNA topoisomerase II inhibitors, antimetabolites, and PARP1 inhibitors for a non-myeloid malignancy. Topoisomerase inhibitors are associated with MN-pCT after a latency period of 1 to 3 years; alkylating agents and radiation are associated with MN-pCT after a latency period of 5 to 7 years. Interestingly, this patient developed myeloid sarcoma in a previously irradiated area within 2 years. Cisplatin was discontinued after 2 doses due to side effect complications and is unlikely to be the culprit. Pembrolizumab is not considered to be a cytotoxic therapy and has not been reported to be associated with MN-pCT, however, the latency period for radiation-induced MN-pCT is unusually short in this patient and this raises the possibility of a Pembrolizumab-induced secondary myeloid neoplasm; additional investigation with other patients on this medication with second subsequent malignancies is required.