Effects of protein kinase C inhibitor, staurosporine derivative CGP 41 251, on cell cycle, DNA synthesis and drug uptake in neoplastic cell lines

Sedlák, J; Hunáková, Ľuba; Duraj, J; Chorváth, B; Novotný, Ladislav

doi:10.1097/00001813-199502000-00008

Cited by 17 publications

(6 citation statements)

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“…As a derivative of staurosporine, midostaurin was also identified to have the capacity to increase doxorubicin accumulation in doxorubicin-resistant cell line A2780/Adr. Meanwhile, midostaurin also acted as a reversal reagent in P-gp mediated leukemia resistance (41, 42). Budworth et al (43) have explored the reversal effects of midostaurin on P-gp mediated breast cancer MCF7/Adr cell line resistance and Beltran et al (44) have confirmed that such an effect of midostaurin was related to alterions in the phosphorylation of P-gp.…”

Section: Discussionmentioning

confidence: 99%

Midostaurin Reverses ABCB1-Mediated Multidrug Resistance, an in vitro Study

Yang

Cai

et al. 2019

Front. Oncol.

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Overexpression of ABC transporters in cancer cells is an underlying mechanism of multidrug resistance (MDR), leading to insensitive response to chemotherapeutic strategies. Thus, MDR is often results in treatment failure in the clinic. In this study, we found midostaurin, a Food and Drug Administration (FDA)-approved anti-leukemia drug, can antagonize ATP-binding cassette subfamily B member 1 (ABCB1)-mediated MDR. Our results indicated that midostaurin has the capacity to antagonize ABCB1-mediated MDR, while no significant reversal effect was found on ATP-binding cassette subfamily G member 2 (ABCG2)-mediated MDR. Our subsequent resistance mechanism studies showed that midostaurin directly inhibited the efflux function of the ABCB1 transporter without alteration of the expression level or the subcellular localization of ABCB1 transporter. In addition, midostaurin inhibited the ATPase activity of ABCB1 transporter in a dose-dependent manner. Moreover, our in silico docking study predicted that midostaurin could interact with the substrate-binding sites of ABCB1 transporter. This novel finding could provide a promising treatment strategy that co-administrating midostaurin with anticancer drugs in the clinic could overcome MDR and improve the efficiency of cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Midostaurin Reverses ABCB1-Mediated Multidrug Resistance, an in vitro Study

Yang

Cai

et al. 2019

Front. Oncol.

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“…at 1,000 rpm). Apoptosis was detected by the flow cytometric analysis as pre‐G 0 (hypodiploid) cells in a propidium iodide‐stained, detergent‐permeabilized cell population as described by Sedlák et al . (1995).…”

Section: Methodsmentioning

confidence: 99%

Cytotoxic and DNA‐Damaging Effects of Diterpenoid Quinones from the Roots of Salvia officinalis L. on Colonic and Hepatic Human Cells Cultured in vitro

Slameñová

Maśterová

Lábaj

et al. 2004

Basic Clin Pharma Tox

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Three diterpenoid quinones (royleanone- SAR 3, horminone- SAR 26, and acetyl horminone- SAR 43) isolated from the roots of Salvia officinalis L. were tested for their cytotoxic and DNA-damaging activity in human colon carcinoma cells Caco-2 and human hepatoma cells HepG2 cultured in vitro. Cytotoxicity was measured by the trypan blue exclusion technique and induction of apoptosis was evaluated by flow immunofluorocytometry after 30-300 min. exposure of HepG2 and Caco-2 cells to diterpenoid quinones and following 24 hr post-incubation in the culture medium. Induction of DNA breaks was measured after 60 min. exposure of cells to different concentrations of the compounds studied by the alkaline elution of DNA and by the Comet assay. Though all the quinones tested decreased the viability of the cells studied proportionally to the concentration and to the time of treatment (cytotoxicity= 30-60%), the increased level of apoptotic nuclei comparable to the level of apoptotic nuclei induced by a topoisomerase I inhibitor was proved only in HepG2 cells treated with 1x10(-4) mol/l SAR 26 or SAR 43. Either no or marginal increase of the level of apoptotic nuclei was observed in SAR 3-treated HepG2 cells and in SAR 3-, SAR 26- or SAR 43-treated Caco-2 cells. All compounds tested induced creation of DNA strand breaks in both cell types at concentrations >1x10(-7)-1x10(-6) mol/l. The occurrence of DNA strand breaks at different pH values as well as the kinetics of DNA breaks rejoining were evaluated only in colonic cells Caco-2. The Comet assay processed in parallel at pH 13.0 and pH 12.1 showed that strand breaks detected in SARs-treated colonic Caco-2 cells originated from alkali-labile sites, as induced DNA lesions were converted to DNA strand breaks only under strong alkaline conditions. The kinetics of DNA rejoining revealed that SARs-induced DNA breaks were repaired very slowly.

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“…Although there are several reports of PKC 412-induced death with apoptotic features in certain tumor-derived cells [29,[34][35][36][37], to our knowledge, there has been no detailed investigation concerning the involvement of apoptotic mechanisms in response to the treatment of lung cancer-derived cells with this drug. Following treatment with this kinase inhibitor an increase in central necrosis and appearance of condensed nuclei was observed in human NSCLC inoculated in mice, suggesting the involvement of apoptotic cell death in the reduction of tumor growth [34].…”

Section: Introductionmentioning

confidence: 99%