Causing DNA damage and stopping DNA repair – Vitamin D supplementation with Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors may cause selective cell death of cancer cells: A novel therapeutic paradigm utilizing elevated copper levels within the tumour

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

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A radiosensitizer, gallotannin-rich extract from Bouea macrophylla seeds, inhibits radiation-induced epithelial-mesenchymal transition in breast cancer cells

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03363-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jiraporn Kantapan ◽

Siwaphon Paksee ◽

Aphidet Duangya ◽

Padchanee Sangthong ◽

Sittiruk Roytrakul ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Cell Death ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Cell Lines ◽

Mesenchymal Transition ◽

Mammosphere Formation ◽

Radiation Induced

Abstract Background Radioresistance can pose a significant obstacle to the effective treatment of breast cancers. Epithelial–mesenchymal transition (EMT) is a critical step in the acquisition of stem cell traits and radioresistance. Here, we investigated whether Maprang seed extract (MPSE), a gallotannin-rich extract of seed from Bouea macrophylla Griffith, could inhibit the radiation-induced EMT process and enhance the radiosensitivity of breast cancer cells. Methods Breast cancer cells were pre-treated with MPSE before irradiation (IR), the radiosensitizing activity of MPSE was assessed using the colony formation assay. Radiation-induced EMT and stemness phenotype were identified using breast cancer stem cells (CSCs) marker (CD24−/low/CD44+) and mammosphere formation assay. Cell motility was determined via the wound healing assay and transwell migration. Radiation-induced cell death was assessed via the apoptosis assay and SA-β-galactosidase staining for cellular senescence. CSCs- and EMT-related genes were confirmed by real-time PCR (qPCR) and Western blotting. Results Pre-treated with MPSE before irradiation could reduce the clonogenic activity and enhance radiosensitivity of breast cancer cell lines with sensitization enhancement ratios (SERs) of 2.33 and 1.35 for MCF7 and MDA-MB231cells, respectively. Pretreatment of breast cancer cells followed by IR resulted in an increased level of DNA damage maker (γ-H2A histone family member) and enhanced radiation-induced cell death. Irradiation induced EMT process, which displayed a significant EMT phenotype with a down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker vimentin in comparison with untreated breast cancer cells. Notably, we observed that pretreatment with MPSE attenuated the radiation-induced EMT process and decrease some stemness-like properties characterized by mammosphere formation and the CSC marker. Furthermore, pretreatment with MPSE attenuated the radiation-induced activation of the pro-survival pathway by decrease the expression of phosphorylation of ERK and AKT and sensitized breast cancer cells to radiation. Conclusion MPSE enhanced the radiosensitivity of breast cancer cells by enhancing IR-induced DNA damage and cell death, and attenuating the IR-induced EMT process and stemness phenotype via targeting survival pathways PI3K/AKT and MAPK in irradiated breast cancer cells. Our findings describe a novel strategy for increasing the efficacy of radiotherapy for breast cancer patients using a safer and low-cost natural product, MPSE.

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MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1903150116 ◽

2019 ◽

Vol 116 (35) ◽

pp. 17438-17443 ◽

Cited By ~ 6

Author(s):

Gayathri Srinivasan ◽

Elizabeth A. Williamson ◽

Kimi Kong ◽

Aruna S. Jaiswal ◽

Guangcun Huang ◽

...

Keyword(s):

Dna Repair ◽

Cancer Cells ◽

Synthetic Lethality ◽

Negative Regulator ◽

Nonhomologous End Joining ◽

Chromosomal Translocations ◽

Replication Forks ◽

Repair Pathway ◽

End Joining ◽

Parp1 Inhibitors

Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223–3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.

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Evaluation of DNA Damage, DNA Repair, Oxidative Stress, and Cell Death Caused by Helicobacter pylori in Human Adenocarcinoma Cells

SSRN Electronic Journal ◽

10.2139/ssrn.3972034 ◽

2021 ◽

Author(s):

DİDEM ORAL ◽

ÜNZİLE SUR ◽

gizem özkemahlı ◽

Anıl Yirüna ◽

N. DİLARA ZEYBEK ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Cell Death ◽

Dna Repair ◽

Helicobacter Pylori ◽

Adenocarcinoma Cells

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Advances and perspectives of PARP inhibitors

Experimental Hematology and Oncology ◽

10.1186/s40164-019-0154-9 ◽

2019 ◽

Vol 8 (1) ◽

Cited By ~ 15

Author(s):

Ming Yi ◽

Bing Dong ◽

Shuang Qin ◽

Qian Chu ◽

Kongming Wu ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Genome Instability ◽

Single Gene ◽

High Sensitivity ◽

Lethal Effect ◽

Single Strand Break ◽

Synthetic Lethal ◽

Increased Risk

Abstract DNA damage repair deficiency leads to the increased risk of genome instability and oncogenic transformation. In the meanwhile, this deficiency could be exploited for cancer treatment by inducing excessive genome instability and catastrophic DNA damage. Continuous DNA replication in cancer cells leads to higher demand of DNA repair components. Due to the oncogenic loss of some DNA repair effectors (e.g. BRCA) and incomplete DNA repair repertoire, some cancer cells are addicted to certain DNA repair pathways such as Poly (ADP-ribose) polymerase (PARP)-related single-strand break repair pathway. The interaction between BRCA and PARP is a form of synthetic lethal effect which means the simultaneously functional loss of two genes lead to cell death, while defect in any single gene has a slight effect on cell viability. Based on synthetic lethal theory, Poly (ADP-ribose) polymerase inhibitor (PARPi) was developed aiming to selectively target cancer cells harboring BRCA1/2 mutations. Recently, a growing body of evidence indicated that a broader population of patients could benefit from PARPi therapy far beyond those with germline BRCA1/2 mutated tumors. Numerous biomarkers including homologous recombination deficiency and high level of replication pressure also herald high sensitivity to PARPi treatment. Besides, a series of studies indicated that PARPi-involved combination therapy such as PARPi with additional chemotherapy therapy, immune checkpoint inhibitor, as well as targeted agent had a great advantage in overcoming PARPi resistance and enhancing PARPi efficacy. In this review, we summarized the advances of PARPi in clinical application. Besides, we highlighted multiple promising PARPi-based combination strategies in preclinical and clinical studies.

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WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors

Cells ◽

10.3390/cells8101258 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1258 ◽

Cited By ~ 5

Author(s):

Kamila Burdova ◽

Radka Storchova ◽

Matous Palek ◽

Libor Macurek

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Homologous Recombination ◽

Cancer Cells ◽

Genotoxic Stress ◽

Parp Inhibitors ◽

Cell Cycle Checkpoint ◽

Dna Lesion ◽

Cycle Checkpoint ◽

G2 Cells

Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

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A ”Clickable” Probe for Active MGMT in Glioblastoma Demonstrates Two Discrete Populations of MGMT

Cancers ◽

10.3390/cancers12020453 ◽

2020 ◽

Vol 12 (2) ◽

pp. 453 ◽

Cited By ~ 1

Author(s):

Sudhir Raghavan ◽

David S. Baskin ◽

Martyn A. Sharpe

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Dna Adducts ◽

Alkylating Agents ◽

Chemotherapeutic Agents ◽

Dna Alkylation ◽

Methylated Dna ◽

Methylguanine Methyltransferase ◽

Discrete Populations

Various pathways can repair DNA alkylation by chemotherapeutic agents such as temozolomide (TMZ). The enzyme O6-methylguanine methyltransferase (MGMT) removes O6-methylated DNA adducts, leading to the failure of chemotherapy in resistant glioblastomas. Because of the anti-chemotherapeutic activities of MGMT previously described, estimating the levels of active MGMT in cancer cells can be a significant predictor of response to alkylating agents. Current methods to detect MGMT in cells are indirect, complicated, time-intensive, or utilize molecules that require complex and multistep chemistry synthesis. Our design simulates DNA repair by the transfer of a clickable propargyl group from O6-propargyl guanine to active MGMT and subsequent attachment of fluorescein-linked PEG linker via ”click chemistry.” Visualization of active MGMT levels reveals discrete active and inactive MGMT populations with biphasic kinetics for MGMT inactivation in response to TMZ-induced DNA damage.

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