Targeting DNA repair in cancer: current state and novel approaches

Klinakis, Apostolos; Karagiannis, Dimitris; Ράμπιας, Θεόδωρος

doi:10.1007/s00018-019-03299-8

Cited by 67 publications

(55 citation statements)

References 260 publications

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“…Since DNA repair pathway genes were significantly increased in BOLD-100 treated cells, we compared total cellular ROS in untreated and treated cells. ROS can induce DNA damage and trigger a complex signaling mechanism called the DNA damage response (DDR) that is used by the cell to reset genomic stability [ 23 ]. In MCF7(2), MDA-MB-231 and MDA-MB-468 cells, treatment with BOLD-100 increased ROS levels in a dose-dependent manner ( Figure 4 A–C) compared with vehicle treated cells (negative control).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of DNA Repair Pathways and Induction of ROS Are Potential Mechanisms of Action of the Small Molecule Inhibitor BOLD-100 in Breast Cancer

Bakewell

Conde

Fallah

et al. 2020

Cancers

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BOLD-100, a ruthenium-based complex, sodium trans-[tetrachloridobis (1H-indazole) ruthenate (III)] (also known as IT-139, NKP1339 or KP1339), is a novel small molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity in a phase I clinical trial. BOLD-100 has been reported to inhibit the upregulation of the endoplasmic reticulum stress sensing protein GRP78. However, response to BOLD-100 varies in different cancer models and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that BOLD-100 induces cytostatic rather than cytotoxic effects as a monotherapy. To understand BOLD-100-mediated signaling mechanism in breast cancer cells, we used estrogen receptor positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models. At 100 μM, BOLD-100 significantly reduced cell proliferation and expression of genes involved in the DNA repair pathway. BOLD-100 also induced reactive oxygen species (ROS) and phosphorylation of histone H2AX, gamma-H2AX (Ser139), suggesting disruption of proper DNA surveillance. In estrogen receptor negative (ER−) breast cancer cells, combination of BOLD-100 with a PARP inhibitor, olaparib, induced significant inhibition of cell growth and xenografts and increased gamma-H2AX. Thus, BOLD-100 is a novel DNA repair pathway targeting agent and can be used with other chemotherapies in ER− breast cancer.

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Section: Resultsmentioning

confidence: 99%

Inhibition of DNA Repair Pathways and Induction of ROS Are Potential Mechanisms of Action of the Small Molecule Inhibitor BOLD-100 in Breast Cancer

Bakewell

Conde

Fallah

et al. 2020

Cancers

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“…The normal cell cycle can be modulated by many different factors, thus leading to alterations in cell proliferation which represent important features of cancer cells. Usually, after a genome damage, a DNA damage response (DDR) occurs, followed by the activation of DNA damage checkpoints (G1 and G2 phases), wherein cell cycle is blocked, thus restraining chromosome segregation until the damage could be fixed, and DNA repair systems are stimulated [89,90].…”

Section: Discussionmentioning

confidence: 99%

Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by β-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention

Sotto

Giacomo

Rubini

et al. 2020

Cells

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Cholangiocarcinoma (CCA) is an aggressive group of biliary tract cancers, characterized by late diagnosis, low effective chemotherapies, multidrug resistance, and poor outcomes. In the attempt to identify new therapeutic strategies for CCA, we studied the antiproliferative activity of a combination between doxorubicin and the natural sesquiterpene β-caryophyllene in cholangiocarcinoma Mz-ChA-1 cells and nonmalignant H69 cholangiocytes, under both long-term and metronomic schedules. The modulation of STAT3 signaling, oxidative stress, DNA damage response, cell cycle progression and apoptosis was investigated as possible mechanisms of action. β-caryophyllene was able to synergize the cytotoxicity of low dose doxorubicin in Mz-ChA-1 cells, while producing cytoprotective effects in H69 cholangiocytes, mainly after a long-term exposure of 24 h. The mechanistic analysis highlighted that the sesquiterpene induced a cell cycle arrest in G2/M phase along with the doxorubicin-induced accumulation in S phase, reduced the γH2AX and GSH levels without affecting GSSG. ROS amount was partly lowered by the combination in Mz-ChA-1 cells, while increased in H69 cells. A lowered expression of doxorubicin-induced STAT3 activation was found in the presence of β-caryophyllene in both cancer and normal cholangiocytes. These networking effects resulted in an increased apoptosis rate in Mz-ChA-1 cells, despite a lowering in H69 cholangiocytes. This evidence highlighted a possible role of STAT3 as a final effector of a complex network regulated by β-caryophyllene, which leads to an enhanced doxorubicin-sensitivity of cholangiocarcinoma cells and a lowered chemotherapy toxicity in nonmalignant cholangiocytes, thus strengthening the interest for this natural sesquiterpene as a dual-acting chemosensitizing and chemopreventive agent.

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“…However, M6620 and AZD6738 were also considered in a recent review in which Mei et al concluded that the use of these inhibitors could serve as a rescue therapy for patients who have experienced tumor progression with PARPi [ 156 ]. The role ATM-inhibitors is otherwise enhanced when used in combination with PARPi [ 157 ]. Indeed, despite the efficacy shown in vivo and in vitro studies, a recent study associated to a phase I clinical trial (NCT02588105) assessed that the use of ATM inhibitors as monotherapy had low antitumor effects [ 150 ], while pre-clinical studies in cell lines showed that the combination of the novel ATM inhibitor AZD0156 in combination with PARPi leads to an increase in DNA double-strand break signaling, cell-cycle arrest, and apoptosis [ 158 ].…”

Section: Targeting Ddr To Defeat Cancermentioning

confidence: 99%

DNA Damage Response and Immune Defense

Nastasi

Mannarino

D’Incalci

2020

IJMS

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DNA damage is the cause of numerous human pathologies including cancer, premature aging, and chronic inflammatory conditions. The DNA damage response (DDR), in turn, coordinates DNA damage checkpoint activation and promotes the removal of DNA lesions. In recent years, several studies have shown how the DDR and the immune system are tightly connected, revealing an important crosstalk between the two of them. This interesting interplay has opened up new perspectives in clinical studies for immunological diseases as well as for cancer treatment. In this review, we provide an overview, from cellular to molecular pathways, on how DDR and the immune system communicate and share the crucial commitment of maintaining the genomic fitness.

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Targeting DNA repair in cancer: current state and novel approaches

Cited by 67 publications

References 260 publications

Inhibition of DNA Repair Pathways and Induction of ROS Are Potential Mechanisms of Action of the Small Molecule Inhibitor BOLD-100 in Breast Cancer

Inhibition of DNA Repair Pathways and Induction of ROS Are Potential Mechanisms of Action of the Small Molecule Inhibitor BOLD-100 in Breast Cancer

Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by β-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention

DNA Damage Response and Immune Defense

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