Reduced accumulation of platinum drugs is not observed in drug-resistant ovarian cancer cell lines derived from cisplatin-treated patients

Stukova, Marina; Hall, Matthew D.; Tsotsoros, Samantha D.; Madigan, James P.; Farrell, Nicholas; Gottesman, Michael M.

doi:10.1016/j.jinorgbio.2015.05.003

Cited by 12 publications

(16 citation statements)

References 28 publications

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“…Therefore, the possibility to use the tested compound in combination with standard cytotoxic drug was investigated in PEO1, cell line representative of high grade serous ovarian cancer harbouring a germline mutation in BRCA2, a gene encoding a protein essential for DNA repair by homologous recombination (HR) 40 , 41 (Supporting Information, Table S4 ). Cisplatin IC 50 value obtained in PEO1 in our experimental conditions was 7.9 ± 0.65 µM (mean ± SEM), in line with literature data 26 , 42 . Compound 8 showed synergism with cisplatin, resulting in a significant reduction of cisplatin IC 50 from 7.9 ± 0.65 to 0.1 ± 0.01 µM, with combination 8 (44 µM) + cisplatin (10 µM) exhibiting the greatest synergistic effect (Table 3 ).…”

Section: Resultssupporting

confidence: 92%

“…Indeed, previous findings have shown that NEK6 and NEK7 may directly regulate microtubule organization 45 , an aspect that makes them attractive targets for drugs that would be complementary to microtubule targeting agents 2 . The IC 50 value for paclitaxel on PEO1 cells was within the range reported in literature 42 , 46 . Results obtained showed a slight synergistic effect at 1 nM paclitaxel, shifting IC 50 paclitaxel from 7.0 ± 0.001 to 0.64 ± 0.057 nM (Table 4 ).…”

Section: Resultssupporting

confidence: 86%

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Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6

Donato

Righino

Filippetti

et al. 2018

Sci Rep

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The NIMA (never in mitosis, gene A)-related kinase-6 (NEK6), which is implicated in cell cycle control and plays significant roles in tumorigenesis, is an attractive target for the development of novel anti-cancer drugs. Here we describe the discovery of a potent ATP site-directed inhibitor of NEK6 identified by virtual screening, adopting both structure- and ligand-based techniques. Using a homology-built model of NEK6 as well as the pharmacophoric features of known NEK6 inhibitors we identified novel binding scaffolds. Twenty-five compounds from the top ranking hits were subjected to in vitro kinase assays. The best compound, i.e. compound 8 ((5Z)-2-hydroxy-4-methyl-6-oxo-5-[(5-phenylfuran-2-yl)methylidene]-5,6-dihydropyridine-3-carbonitrile), was able to inhibit NEK6 with low micromolar IC50 value, also displaying antiproliferative activity against a panel of human cancer cell lines. Our results suggest that the identified inhibitor can be used as lead candidate for the development of novel anti-cancer agents, thus opening the possibility of new therapeutic strategies.

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 86%

Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6

Donato

Righino

Filippetti

et al. 2018

Sci Rep

View full text Add to dashboard Cite

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“…Compared with 30-40% of ovarian cancer patients with platinum-resistance in 2012 [5], the data in 2019 increased to 70-80% [6]. In response to platinum-resistance, most treatments choose platinum-free drugs to increase the drugs sensitivity for patients [7], the drugs available to clinicians have doxorubicin liposome, paclitaxel (aluminum binding type)(hereinafter referred to as nab-P) and so on, they are widely used in clinical practice. nab-P is a kind of paclitaxel in the form of 130 nanoparticles which combines with human albumin, using albumin as carrier and stabilizer, adsorbing on tumor cells through SPARC protein, and then releasing toxicity to kill tumor cells, belongs to targeted chemotherapeutic drugs [8].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The role of Apatinib combined with Paclitaxel (aluminum binding type) in drug-resistant ovarian cancer

Zhao

Wang

et al. 2020

Preprint

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ObjectiveTo assess the antitumor effects and side reactions of different dosages of Paclitaxel (albumin binding) combined with Apatinib in drug-resistant ovarian cancer cell line and xenotransplantation tumor model. MethodsConventional cell experiments were used to evaluate the effects of Apatinib and Paclitaxel (albumin binding), SKOV-3/DDP were selected as research object and divided into 3 groups for study, a): control group, no drug intervention; b): nab-P group, Paclitaxel (albumin binding type) 40 µmol/l; c): Apatinib group, Apatinib 50 µmol/l. The IC-50 value of the drug was detected by MTT test, apoptosis related protein(Bax, bcl-2), vascular related protein(p-VEGFR-2), invasion related protein(MMP-2) expression were detected by Western blot and Cellular immunofluorescence, the invasion and migration ability of tumor cells were detected by Transwell and Cell scratch test. Based on these dates, establishing different dosages of Paclitaxel (albumin binding type) combined with Apatinib, a): Control group, no drug intervention; b): Group-1, Paclitaxel (albumin binding type) 5 µmol/l + Apatinib 10 µmol/l, c): Group-2, Paclitaxel (albumin binding type) 4.5 µmol/l + Apatinib 10 µmol/l, d): Group-3, Paclitaxel (albumin binding type)4 µmol/l + Apatinib 10 µmol/l, the index of combined use was analyzed by Compusyn software, Western blot, Immunofluescence, Transwell, Cell scratch test also were chose to change of inhibition effect. On the other hand, we used xenograft tumor model to verify the results in vivo. BALB/c female nude mice were randomly divided into 4 groups, a): Control group, no drug intervention; b): Paclitaxel (albumin binding type) 20 mg/kg + Apatinib 150 mg/kg, c): Paclitaxel (albumin binding type) 18 mg/kg + Apatinib 150 mg/kg, d): Paclitaxel (albumin binding type) 16 mg/kg + Apatinib 150 mg/kg. The tumor growth curve was analyzed during the test. The apoptosis related protein (Bax, bcl-2), angiogenesis related protein (CD31, p-VEGFR-2) and invasion related protein(MMP-2) were analyzed by Western blot, Immunofluescence and Immunohistochemistry to analysis the effect of antitumor and side reactions Result (1) The IC-50 value of SKOV-3/DDP to paclitaxel (albumin binding type) was 45.53 ± 4.06 µmol/l, while

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“…More importantly, the number of patients who develop platinum-resistance are increasing, compared with 30-40% of OC patients with platinum-resistance in 2012 [5] , the data in 2019 increased to 70-80% [6] . In response to the above phenomena, in clinic, most platinum-free drugs are chosen to improve the sensitivity of the patient itself, such as liposome adriamycin, nab-P and so on [7] . nab-P is based on paclitaxel, and human albumin is added as carrier and stabilizer, and the molecular weight is about 130 nm.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The Role of Apatinib Combined with Paclitaxel (aluminum binding type) in Platinum-resistant Ovarian Cancer

Zhao

Wang

et al. 2020

Preprint

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Objective: To assess the anti-tumor activity and side effects of different dosages of paclitaxel (albumin binding type) (hereinafter referred to as nab-P) combined with Apatinib (hereinafter referred to as AP) in platinum-resistant ovarian cancer cell line and xenograft models.Methods: SKOV-3/DDP cell line was selected as the research object in cytology experiment. Firstly, we divided it into three groups for experiments to explore the individual effects of nab-P and AP. a): Control group, blank control, no drug intervention; b): nab-P group, nab-P 40μmol/l; c): AP group, AP 50μmol/l (Drug doses were IC-50 values that detected by MTT assay). Apoptosis related protein(Bax, bcl-2), vascular related protein(p-VEGFR-2), invasion related protein(MMP-2) expression were detected by Western blot and Cellular immunofluorescence, the invasion ability of tumor cells were detected by Transwell and Cell scratch test. Based on these dates, secondly, establishing different doses of nab-P combined with Ap to explore the curative effect of combination therapy. a): Control group, blank control, no drug intervention; b): Group-1, nab-P 5μmol/l + AP 10μmol/l, c): Group-2, nab-P 4.5μmol/l + AP 10μmol/l, d): Group-3, nab-P 4μmol/l + AP 10μmol/l, e): nab-P group, nab-P 5μmol/l, f): AP group, AP 10μmol/l (MTT assay). The combination index was analyzed by Compusyn software, Western blot, Immunofluescence, Transwell and Cell scratch test also were also chose to observe of inhibition effect. Thirdly, we used xenograft models to verify the results of cytological experiments. Tumor-forming BALB/c female nude mice were randomly divided into 4 groups, a): Control group, no drug intervention, only saline injection, b): nab-P 20mg/kg + AP 150mg/kg , c): nab-P 18mg/kg + AP 150mg/kg, d): nab-P 16mg/kg + AP 150mg/kg(The doses were guided by the pharmaceutical manufacturers). The tumor growth curve was analyzed during the experiment. And the apoptosis related protein (Bax, bcl-2), angiogenesis related protein (CD31, p-VEGFR-2) and invasion related protein(MMP-2) were observed by Western blot, Immunofluescence and Immunohistochemistry to analysis the ant-tumor effects. The quality of life in nude mice were observed to analysed the drug-induced side effects.Result: In the separate medication section, (1) The IC-50 value of nab-P was 45.53±4.06 μmol/l, while the AP was 50.66±4.96 umol/L (48h). (2) The expressions of bcl-2 (nab-P group, AP group), p-VEGFR-2 (AP group), MMP-2(nab-P group, AP group) were higher than Control group, while Bax(nab-P group, AP group) lower (P<0.01). (3) The cell invasive ability was decreased after the nab-P and AP intervation (P<0.01). In the combination medication section, (1) Compusyn showed the Combination index (Cl) were all below 1 (Cl<1), that means nab-P and AP are synergism. (2) The combination IC-50 value was nab-P 5.28 μmol/l+AP 10.56 μmol/l (48h). (3) In the detection of related protein expression, the combination of drugs can improve the anti-tumor effect, otherwise, after combined with AP, when nab-P were reduced dose in proper quantity, there were no obvious different in drug effect. (4) After reducing the doses of nab-P, the average food intake of nude mice increased from 4.50 g±0.17 to 5.55 g±0.13, and the one-hour activity increased from 6.11min ±0.16 to 6.34 min ±0.13.Conclusion: nab-P, a chemotherapeutic agent, can play an anti-tumor role in platinum-resistant ovarian cancer, but it can cause adverse effects that increase with dose. When combined with AP, the two drugs have synergistic effect, which can improve the anti-tumor effects of single drug. In addition, when combined with AP, the doses of nab-P can be appropriately reduced under the standard of recommended to reduce the toxicity of chemotherapy drugs, without affecting the anti-tumor effect.

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Reduced accumulation of platinum drugs is not observed in drug-resistant ovarian cancer cell lines derived from cisplatin-treated patients

Cited by 12 publications

References 28 publications

Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6

Identification and antitumor activity of a novel inhibitor of the NIMA-related kinase NEK6

WITHDRAWN: The role of Apatinib combined with Paclitaxel (aluminum binding type) in drug-resistant ovarian cancer

WITHDRAWN: The Role of Apatinib Combined with Paclitaxel (aluminum binding type) in Platinum-resistant Ovarian Cancer

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