Sensitization of Cancer Cells to Radiation and Topoisomerase I Inhibitor Camptothecin Using Inhibitors of PARP and Other Signaling Molecules

Matsuno, Yusuke; Hyodo, Mai; Fujimori, Haruka; Shimizu, Atsuhiro; Yoshioka, Kenichi

doi:10.3390/cancers10100364

Cited by 22 publications

(14 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The molecular basis of p53-dependent apoptotic pathway in HCC cells was also analyzed by the expression of apoptosis markers, that is, cleaved caspase-3 and cleaved PARP functioned in the execution of the intrinsic mitochondrial apoptotic pathway. The proteolytic cleavage of PARP facilitated cellular disassembly and undergone apoptosis[33,34]. According to our data, with the presence of p53, overexpression of GAS2 could increase the level of cleaved caspase-3 and cleaved PARP induced by etoposide.…”

Section: Discussionmentioning

confidence: 68%

Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis

Zhu

Cheng

Chan

et al. 2019

WJG

View full text Add to dashboard Cite

BACKGROUND Growth arrest-specific gene 2 (GAS2) plays a role in modulating in reversible growth arrest cell cycle, apoptosis, and cell survival. GAS2 protein is universally expressed in most normal tissues, particularly in the liver, but is depleted in some tumor tissues. However, the functional mechanisms of GAS2 in hepatocellular carcinoma (HCC) are not fully defined. AIM To investigate the function and mechanism of GAS2 in HCC. METHODS GAS2 expression in clinic liver and HCC specimens was analyzed by real-time PCR and western blotting. Cell proliferation was analyzed by counting, MTS, and colony formation assays. Cell cycle analysis was performed by flow cytometry. Cell apoptosis was investigated by Annexin V apoptosis assay and western blotting. RESULTS GAS2 protein expression was lower in HCC than in normal tissues. Overexpression of GAS2 inhibited the proliferation of HCC cells with wide-type p53, while knockdown of GAS2 promoted the proliferation of hepatocytes ( P < 0.05). Furthermore, GAS2 overexpression impeded the G1-to-S cell cycle transition and arrested more G1 cells, particularly the elevation of sub G1 ( P < 0.01). Apoptosis induced by GAS2 was dependent on p53, which was increased by etoposide addition. The expression of p53 and apoptosis markers was further enhanced when GAS2 was upregulated, but became diminished upon downregulation of GAS2. In the clinic specimen, GAS2 was downregulated in more than 60% of HCCs. The average fold changes of GAS2 expression in tumor tissues were significantly lower than those in paired non-tumor tissues ( P < 0.05). CONCLUSION GAS2 plays a vital role in HCC cell proliferation and apoptosis, possibly by regulating the cell cycle and p53-dependent apoptosis pathway.

show abstract

Section: Discussionmentioning

confidence: 68%

Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis

Zhu

Cheng

Chan

et al. 2019

WJG

View full text Add to dashboard Cite

show abstract

“…PARP inhibitors were originally developed to sensitize tumors to the effects of DNA damaging agents, including ionizing radiation, temozolomide, and topotecan. In fact, PARP inhibitors have successfully sensitized tumors to radiation and to camptothecin, a topoisomerase I inhibitor [62,63]. However, the combination of gemcitabine, doxorubicin, and taxan showed no significant synergies [64,65].…”

Section: Combination Effect Of Conventional Chemotherapy According Tomentioning

confidence: 99%

“…At this point, the PARP inhibitor lets the trapping of TOP1cc continue by preventing TDP1 from removing the covalent attachment of TOP1, as PARP1 recruits TDP1 through PARylation. This is due to the regulation of PARylation activity by PARP inhibitors, which has the same effect on all PARP inhibitors developed in the clinic [63,77,79]. Those applying combination therapies of PARP inhibitors and chemotherapy within the clinic should carefully consider the mechanism(s) of action prior to selecting the drug.…”

Section: Nct01924533 [32] IIImentioning

confidence: 99%

PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation

Min

2020

Cancers

109

105

View full text Add to dashboard Cite

Poly (ADP-ribose) polymerase (PARP) 1 is an essential molecule in DNA damage response by sensing DNA damage and docking DNA repair proteins on the damaged DNA site through a type of posttranslational modification, poly (ADP-Ribosyl)ation (PARylation). PARP inhibitors, which inhibit PARylation through competitively binding to NAD+ binding site of PARP1 and PARP2, have improved clinical benefits for BRCA mutated tumors, leading to their accelerated clinical application. However, the antitumor activities of PARP inhibitors in clinical development are different, due to PARP trapping activity beyond blocking PARylation reactions. In this review, we comprehensively address the current state of knowledge regarding the mechanisms of action of PARP inhibitors. We will also discuss the different effects of PARP inhibitors in combination with cytotoxic chemotherapeutic agents regarding the mechanism of regulating PARylation.Cancers 2020, 12, 394 2 of 16 be true, PARP inhibitors that inhibit DDR resulted in improved clinical benefits and became standard therapy [9][10][11]. To date, four PARP inhibitors have been approved by the FDA and are being applied clinically. However, while all PARP inhibitors inhibit PARP catalytic activities, they have different cytotoxicities. Therefore, the anti-tumor effects of the PARP inhibitors have been suggested to be due to PARP trapping, as well as the inhibition of the enzymatic activities [12,13].The catalytic inhibition and trapping effects of PARP are tightly regulated, and the cytotoxicity of each mechanism can cause different reactivities. Therefore, in this review, based on mechanisms of PARP, we intend to examine the difference of anti-tumor effect of the PARP inhibitors and the current aspect of the roles in combination treatment. PARPs and PARylationPoly (ADP-ribose) polymerase (PARP) is a family of 17 proteins in mammals, encoded by different genes, but with a conserved catalytic domain. Other than the catalytic domain, PARP family members contain one or more other motifs or domains, including zinc fingers, a breast cancer-susceptibility protein (BRCA) C-terminus-like (BRCT) motifs, ankyrin repeats, macro domains, and WWE domains [14] ( Figure 1A). PARP1 was the first family member identified and has a critical role in SSB repair through the metabolism of recruiting and dissociating repair proteins by PARylation. In addition to DNA damage repair, PARP1 has important roles in a various range of cellular processes from cell proliferation to cell death, due to having diverse substrates like nuclear proteins involved in transcriptional regulation, apoptotic cell death, chromatin decondensation, inflammation, and cell cycle regulation [15,16]. PARP1 has a total molecular weight of 113 kDa and contains seven independent domains ( Figure 1B) [5,17]. The N-terminus is the DNA binding domain (residues 1-353), which contains three zinc-finger DNA-binding domains, ZnFI, ZnFII, and ZnFIII, which are responsible for recognizing sites of damaged DNA and binding through allosteric activation. ...

show abstract

“…PARP inhibitors were initially designed to make tumors vulnerable to DNA-damaging agents such as radiation and chemotherapeutic agents. Indeed, PARP inhibitors succeeded in sensitizing tumor cells to topoisomerase 1 inhibitors (e.g., camptothecin) and radiation [141]. However, it has been reported that the combination of PARP inhibitors with doxorubicin, gemcitabine, and taxan has no significant synergistic effects [142].…”

Section: Combination Therapies Ddr Inhibitors and Dna-damaging Agentsmentioning

confidence: 99%

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

et al. 2020

View full text Add to dashboard Cite

Synthetic lethality is a lethal phenomenon in which the occurrence of a single genetic event is tolerable for cell survival, whereas the co-occurrence of multiple genetic events results in cell death. The main obstacle for synthetic lethality lies in the tumor biology heterogeneity and complexity, the inadequate understanding of synthetic lethal interactions, drug resistance, and the challenges regarding screening and clinical translation. Recently, DNA damage response inhibitors are being tested in various trials with promising results. This review will describe the current challenges, development, and opportunities for synthetic lethality in cancer therapy. The characterization of potential synthetic lethal interactions and novel technologies to develop a more effective targeted drug for cancer patients will be explored. Furthermore, this review will discuss the clinical development and drug resistance mechanisms of synthetic lethality in cancer therapy. The ultimate goal of this review is to guide clinicians at selecting patients that will receive the maximum benefits of DNA damage response inhibitors for cancer therapy.

show abstract

Sensitization of Cancer Cells to Radiation and Topoisomerase I Inhibitor Camptothecin Using Inhibitors of PARP and Other Signaling Molecules

Cited by 22 publications

References 90 publications

Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis

Growth arrest-specific gene 2 suppresses hepatocarcinogenesis by intervention of cell cycle and p53-dependent apoptosis

PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

Contact Info

Product

Resources

About