Neocarzinostatin (zinostatin) / Astellas - LARVOL DELTA

Gene Studies About Development of Renal Cell Carcinoma (ASGCT 2025) - "Gamma irradiation, doxorubicin, or neocarzinostatin was applied to cause DSBs in renal cells, which were labeled by γH2AX antibodies. Jade-1 participated in DSBs process, and pVHL did not enhance the overlapping between Jade-1 and DSBs. This implies that Jade-1 may not require pVHL in DNA repair process. DSBs upregulated Jade-1 protein level, and pVHL inhibited this elevation."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • VHL

Location of oncogene-induced DNA damage sites revealed by quantitative analysis of a DNA counterstain. (PubMed, Eur Biophys J) - "Conversely, when DNA damage is induced by the radiomimetic agent neocarzinostatin (NCS), the foci appear more evenly distributed in euchromatic and heterochromatic regions. These findings underscore the complex interplay between oncogene activation and chromatin organization, revealing how disruptions in DNA damage distribution can contribute to genomic instability and offering new insights for targeting DNA repair mechanisms in cancer therapies."

Journal • Acute Promyelocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • PML • RARA

Detection of γ-H2A.X for Rapid Assessment of Genotoxic Agent-induced Double-strand DNA Breaks by Immunofluorescence. (PubMed, Methods Mol Biol) - "In this chapter, we describe a simple and efficient immunofluorescence (IF) procedure for detecting DSB formation in U-2 OS cells treated with genotoxic agents. This technique does not require an expensive laboratory setup and can also be used to detect the formation of foci of additional repair factors using appropriate labeling."

Journal

Quantitative Single-Cell Comparison of Sensitization to Radiation and a Radiomimetic Drug for Diverse Gold Nanoparticle Coatings. (PubMed, Small Sci) - "Herein, single-cell analysis of two cell lines in response to megavolt irradiation and a radiomimetic drug, neocarzinostatin (NCS) after coculture with gold NPs with different surface coatings, polyethylene glycol (AuPEG), PEG, and transferrin (AuT) or silica (AuSiO2), is reported...While NPs contribute to radiosensitization (or enhancing/impeding chemotherapeutic drug activity), due to cell and cell line heterogeneity, the ultimate radiosensitivity of a cell appears to be dominated by its inherent radiosensitivity and how this cell-regulated response is manipulated by NPs. This is evidenced through comparison of radiobiological response of cells with equivalent NP association rather than equivalent coculture conditions."

Journal • Oncology

Gastrointestinal side effects in hepatocellular carcinoma patients receiving transarterial chemoembolization: a meta-analysis of 81 studies and 9495 patients. (PubMed, Ther Adv Med Oncol) - "The type of chemotherapy agent influenced prevalence of GI-side effects, with high prevalences observed for agents such as zinostatin and cisplatin. This meta-analysis synthesizes current evidence on managing GI side effects in TACE. Standardizing reporting and developing effective management strategies are crucial to improving patient outcomes."

Adverse events • Journal • Retrospective data • Gastrointestinal Disorder • Hepatocellular Cancer • Oncology • Pain • Solid Tumor

Promising Effects of Novel Supplement Formulas in Preventing Skin Aging in 3D Human Keratinocytes. (PubMed, Nutrients) - "The foci count revealed that a 24-h treatment with the supplement did not induce DNA damage, and significantly reduced DNA damage in cells exposed to neocarzinostatin for 2 h. Three of the simpler formulations showed similar results. Moreover, the antioxidant activity was tested using a recently developed whole cell-based chemiluminescent bioassay; results showed that a 24-h treatment with the supplement and three simpler formulations significantly reduced intracellular H2O2 after pro-oxidant injury, thus suggesting their possible antiaging effect. This study's originality lies in the use of a 3D human keratinocyte cell model and a combination of natural ingredients targeting DNA damage and oxidative stress, providing a robust evaluation of their anti-aging potential."

Journal • Oncology • TP53BP1

Absolute quantification of DNA damage response proteins. (PubMed, Genes Environ) - "The approach provided quantitative insights into protein dynamics in DNA damage response."

Journal • MDC1 • MRE11A • RAD50 • RAD51 • TP53BP1 • XRCC5 • XRCC6

SMYD3 Modulates AMPK-mTOR Signaling Balance in Cancer Cell Response to DNA Damage. (PubMed, Cells) - "Moreover, we found that SMYD3 can methylate AMPK at the evolutionarily conserved residues Lys411 and Lys424. Overall, our data revealed that SMYD3 can act as a bridge between the AMPK and mTOR pathways upon neocarzinostatin-induced DNA damage in gastrointestinal and breast cancer cells."

Journal • Breast Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • SMYD3 • TSC2

Identifying Suitable Reference Gene Candidates for Quantification of DNA Damage-Induced Cellular Responses in Human U2OS Cell Culture System. (PubMed, Biomolecules) - "We evaluated the expressional changes of eight well-known housekeeping genes (i.e., 18S rRNA, B2M, eEF1α1, GAPDH, GUSB, HPRT1, PPIA, and TBP) following treatment with the DNA-damaging agents that are most frequently used: ultraviolet B (UVB) non-ionizing irradiation, neocarzinostatin (NCS), and actinomycin D (ActD). In summary, this is the first systematic study using a U2OS cell culture system that offers convincing evidence for housekeeping gene selection following treatment with various DNA-damaging agents. Here, we unravel an indispensable issue for performing and assessing trustworthy DNA damage-related differential gene expressional analyses, and we create a "zero set" of potential reference gene candidates."

Journal • Preclinical • B2M • EEF1A1 • GAPDH • HPRT1 • PPIA

UbcH5c-dependent activation of DNA-dependent protein kinase in response to replication-mediated DNA double-strand breaks. (PubMed, Biochem Biophys Res Commun) - "Knockdown of UbcH5c suppressed DNA-PK activation caused by CPT, but not by the radio-mimetic drug neocarzinostatin...These results suggest that UbcH5c regulates DNA-PK activation in response to one-ended DSBs caused by replication fork collapse. To our knowledge, this is the first report of a DSB repair-related factor that is differentially involved in the response to one- and two-ended DSBs."

Journal • Targeted Protein Degradation

Changes in calpain-2 expression during glioblastoma progression predisposes tumor cells to temozolomide resistance by minimizing DNA damage and p53-dependent apoptosis. (PubMed, Cancer Cell Int) - "TMZ-induced cell death in the presence of calpain-2 expression appears to favor DNA repair and promote cell survival. We conclude from our experiments that calpain-2 expression represents a proteomic mode that is associated with higher resistance via "priming" GBM cells to TMZ chemotherapy. Thus, calpain-2 could serve as a prognostic factor for GBM outcome."

Journal • Tumor cell • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CASP3 • NF-κβ • TP53

ATM-SPARK: A GFP phase separation-based activity reporter of ATM. (PubMed, Sci Adv) - "Furthermore, BGT226 sensitizes cancer cells to the radiomimetic drug neocarzinostatin, suggesting that BGT226 might be combined with radiotherapeutic treatment. ATM-SPARK achieves large dynamic range, bright fluorescence, and simple signal pattern."

Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency

Enhanced Permeability and Retention Effect as a Ubiquitous and Epoch-Making Phenomenon for the Selective Drug Targeting of Solid Tumors. (PubMed, J Pers Med) - "In 1979, development of the first polymer drug SMANCS [styrene-co-maleic acid (SMA) copolymer conjugated to neocarzinostatin (NCS)] by Maeda and colleagues was a breakthrough in the cancer field...In this review, we focus on the dynamics of the EPR effect and restoring tumor blood flow by using EPR effect enhancers. We also discuss new applications of EPR-based nanomedicine in boron neutron capture therapy and photodynamic therapy for solid tumors."

Journal • Review • Oncology • Solid Tumor

Cleavage of Early Mouse Embryo with Damaged DNA. (PubMed, Int J Mol Sci) - "It seems that the phenomenon creates a predisposition to a segregation disorder of condensed chromatin that results in the formation of micronuclei in the developmental stages following the first cleavage. We conclude that zygote tolerates a certain degree of DNA damage and considers its priority to complete the first cleavage stage and continue embryogenesis as far as possible."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Psychiatry

Preferential translation of p53 target genes. (PubMed, RNA Biol) - "In order to separate these passive effects from active regulation of translation efficiency in response to p53 activation, we conducted a comprehensive analysis of translational regulation by comparative analysis of mRNA levels and ribosome densities upon DNA damage induced by neocarzinostatin in wild-type and TP53 HCT116 colorectal carcinoma cells. Thereby, we identified a specific group of mRNAs that are preferentially translated in response to p53 activation, many of which correspond to p53 target genes including MDM2, SESN1 and CDKN1A. By subsequent polysome profile analysis of SESN1 and CDKN1A mRNA, we could demonstrate that p53-dependent translational activation relies on a combination of inducing the expression of translationally advantageous isoforms and trans-acting mechanisms that further enhance the translation of these mRNAs."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDKN1A • MDM2 • TP53

Liposome-Encapsulated Tiancimycin A Is Active against Melanoma and Metastatic Breast Tumors: The Effect of cRGD Modification of the Liposomal Carrier and Tiancimycin A Dose on Drug Activity and Toxicity. (PubMed, Mol Pharm) - "Enediyne natural products, including neocarzinostatin and calicheamicin γ, are used in the form of a copolymer or antibody-drug conjugate to treat hepatomas and leukemia...Because TNM A causes rapid DNA damage, cell cycle arrest, and apoptosis, these nanoparticles exhibited potent cytotoxicity against multiple tumor cells for 8 h. In B16-F10 and KPL-4 xenografts, both nanoparticles showed superior potency over doxorubicin and trastuzumab...In a highly metastatic 4T1 tumor model, cRGD-Lip-TNM A reduced tumor metastasis induced by losartan, a tumor microenvironment-remodeling agent. These findings suggest that targeted delivery of enediynes with unique modes of action may enable more effective translation of anticancer nanomedicines."

Journal • Breast Cancer • Gastrointestinal Cancer • Hematological Malignancies • Hepatocellular Cancer • Leukemia • Melanoma • Oncology • Solid Tumor

Nuclear ceramide is associated with ATM activation in the neocarzinostatin-induced apoptosis of lymphoblastoid cells. (PubMed, Mol Pharmacol) - "Significance Statement We demonstrate that regulation of ceramide with neutral sphingomyelinase (nSMase) and sphingomyelin synthase in the nucleus in double-strand break-mimetic agent neocarzinostatin (NCS)-induced apoptosis. We also showed that ceramide increase in the nucleus plays a role in NCS-induced apoptosis through activation of the ataxia telangiectasia mutated/Mre11/Rad50/Nbs1 complex in human lymphoblastoid cells."

Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • MRE11A

Chemotherapy of HER2- and MDM2-Enriched Breast Cancer Subtypes Induces Homologous Recombination DNA Repair and Chemoresistance. (PubMed, Cancers (Basel)) - "Inhibition of MDM2 expression in the SKBR3 cell line (HER2 subtype) diminished the survival of cancer cells treated with doxorubicin, etoposide, and camptothecin. Moreover, we demonstrated that inhibition of MDM2 expression diminished DNA repair by homologous recombination (HR) and sensitized SKBR3 cells to a PARP inhibitor, olaparib. In H1299 (TP53) cells treated with neocarzinostatin (NCS), overexpression of MDM2 WT or E3-dead MDM2 C478S variant stimulated the NCS-dependent phosphorylation of ATM, NBN, and BRCA1, proteins involved in HR DNA repair...Using a proliferation assay, we showed that overexpression of MDM2 WT, but not MDM2 K454A, led to acquisition of resistance to NCS. The presented results indicate that, following chemotherapy, MDM2 WT was released from MDM2-NBN complex and efficiently degraded, hence allowing extensive HR DNA repair leading to the acquisition of chemoresistance by cancer cells."

Journal • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • BRCA1 • HER-2 • MDM2 • NBN

Challenges and Opportunities to Develop Enediyne Natural Products as Payloads for Antibody-Drug Conjugates. (PubMed, Antib Ther) - "Calicheamicin, the payload of the antibody-drug-conjugates (ADCs) gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin (Besponsa), belongs to the class of enediyne natural products. Since the isolation and structural determination of the neocarzinostatin chromophore in 1985, the enediynes have attracted considerable attention for their value as DNA damaging agents in cancer chemotherapy. Due to their non-discriminatory cytotoxicity towards both cancer and healthy cells, the clinical utilization of enediyne natural products relies on conjugation to an appropriate delivery system, such as an antibody. Here we review the current landscape of enediynes as payloads of first-generation and next-generation ADCs."

Journal • Oncology

Genotoxic stress-activated DNA-PK-p53 cascade and autophagy cooperatively induce ciliogenesis to maintain the DNA damage response. (PubMed, Cell Death Differ) - "Treatment with genotoxic drugs (etoposide, neocarzinostatin, hydroxyurea, or cisplatin) led to ciliogenesis in human retina (RPE1), trophoblast (HTR8), lung (A459), and mouse Leydig progenitor (TM3) cell lines. Besides, inhibition of ciliogenesis by depletion of IFT88 or CEP164 attenuated the genotoxic stress-induced DNA damage response. Thus, our study uncovered the interplay among genotoxic stress, the primary cilium, and the DNA damage response."

Journal

ATM kinase activity is dispensable in mitochondrial autophagy (AACR 2018) - "...Routine ATM kinase activity was performed by FACS analysis following either neocarzinostatin or IR-induced PE-ATMSer1981 and FITC-H2AXSer139 phosphorylations status and reconfirmed by immunoblot assay by probing with phospho-ATMSer1981and ATM targets Kap1Ser824 or Smc1Ser966 phosphorylations...Malignant primary B-cell lymphomas including MCL without detectable ATM, Parkin, Pink1, and Parkin-Ubser65 phosphorylation were resistant to mitophagy. This data provides the first molecular evidence of the role of ATM kinase function in mitophagy in cancer."

IO Biomarker • Mantle Cell Lymphoma

Phosphoproteomics reveals novel modes of function and inter-relationships among PIKKs in response to genotoxic stress. (PubMed, EMBO J) - "We conducted a comprehensive phosphoproteomic analysis in human wild-type and A-T cells treated with the double-strand break-inducing chemical, neocarzinostatin, and validated the results with the targeted proteomic technique, selected reaction monitoring...In A-T cells, partial compensation for ATM absence was provided by ATR and DNA-PK, with distinct roles and kinetics. The results highlight intricate relationships between these PIKKs in the DDR."

Journal • Ataxia • Immunology • Movement Disorders • Primary Immunodeficiency

[VIRTUAL] Hyperactive End Joining Repair Mediates Radiation Resistance in TP53 Deficient Cells (ASTRO 2020) - "Cells were exposed to the radiomimetic Neocarzinostatin (NCS), DNA-PK inhibitor (DNA-PKi, NU7441), or both, and imaged for 72 hours to monitor cell cycle state transitions and DNA damage foci kinetics in individual cells. Our study identifies NHEJ and TMEJ as two targetable DSB end joining pathways that can be suppressed as a strategy to restore radiation sensitivity in TP53 deficient cancers."

Oncology • PCNA • TP53

[VIRTUAL] DNA Double-Strand Breaks of Human Glomerular Endothelial Cell-Induced Collagen Type VI Excretion and Nodular Lesions in Various Kidney Diseases (KIDNEY WEEK 2020) - "In vitro study, we investigated the relationship between DSBs and COL6 excretion and the intracellular signal pathways in human glomerular endothelial cells (HRGECs) using mitomycin C (MMc)-induced DNA damage, and other two agents; Neocarzinostatin (NCS) and camptothecin (CPT). We examined the effect of DSBs response signal pathways, i.e. ATM, ATR and DNA-PK using their specific kinase inhibitors (KU55933, VE-821, Nu7441)... This study showed that DNA damage-sensing kinase of ATR was activated in response to DSBs and induced COL6 secretion of human glomerular endothelial cells. Furthermore, DNA damage may induce the nodular glomerulosclerosis in various kidney diseases. Funding: Government Support - Non-U."

Chronic Kidney Disease • Diabetic Nephropathy • Fibrosis • Glomerulonephritis • Immunology • Nephrology • Renal Disease • ATR

Rucaparib Treatment Alters p53 Oscillations in Single Cells to Enhance DNA-Double-Strand-Break-Induced Cell Cycle Arrest. (PubMed, Cell Rep) - "As a result, combination treatments of the radiomimetic drug neocarzinostatin with rucaparib drove prolonged growth arrest beyond that of DNA damage alone. This study highlights how pharmacological manipulation of DNA repair pathways may be used to alter p53 dynamics to enhance therapeutic regimens."

Journal • Ataxia • Immunology • Movement Disorders • Primary Immunodeficiency • PARP1