Apatone ® induces endometrioid ovarian carcinoma (MDAH 2774) cells to undergo karyolysis and cell death by autoschizis: A potent and safe anticancer treatment

Gilloteaux, Jacques; Lau, Hui-Ching; Gourari, Ioulia; Neal, Deborah; Jamison, James M.; Summers, Jack L.

doi:10.1016/j.tria.2015.10.005

Cited by 5 publications

(5 citation statements)

References 90 publications

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“…A sulforhodamine-B (SRB) assay was used to investigate growth inhibition by Nutlin-3/RG7388 or rucaparib for a panel of wild-type and mutant TP53 ovarian cancer cell lines derived from tumors of different histological subtypes [ 19 – 22 ] (Figure 1 and Table 1 ). The GI 50 values, required concentration of each compound leading to 50% growth inhibition, showed that wild-type TP53 ovarian cancer cell lines were significantly more sensitive to Nutlin-3/RG7388 compared to mutant, which is consistent with their mechanism of action ( p<0.0001 Mann-Whitney test) (Figure 1A & 1B ).…”

Section: Resultsmentioning

confidence: 99%

“…The most interesting finding is that the A2780 cell line was the most sensitive cell line even though among the relevant genes previously implicated in the sensitivity to rucaparib it has only a heterozygous mutation in PTEN (Deletion-In frame, heterozygous, (c.380_388delGAAAGGGAC) (89682879_89682887delAGGGACGAA) ( Supplementary Table 1 ). MDAH-2774 is an ovarian endometrioid tumor with mutant TP53 and KRAS [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

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Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer

et al. 2017

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Ovarian cancer is the seventh most common cancer worldwide for females and the most lethal of all gynecological malignancies. The treatment of ovarian cancer remains a challenge in spite of advances in debulking surgery and changes in both chemotherapy schedules and routes of administration. Cancer treatment has recently been improving with the introduction of targeted therapies to achieve greater specificity and less cytotoxicity. Both PARP inhibitors and MDM2-p53 binding antagonists are targeted therapeutic agents entered into clinical trials. This preclinical study evaluated the effect of Nutlin-3/RG7388 and rucaparib as single agents and in combination together in a panel of ovarian cancer cell lines. Median-drug-effect analysis showed Nutlin-3/RG7388 combination with rucaparib was additive to, or synergistic in a cell type-dependent manner. Mechanism studies showed rucaparib alone had no effect on p53 stabilization or activity. Although treatment with Nutlin-3 or RG7388 induced stabilization of p53 and upregulation of p21WAF1 and MDM2, the addition of rucaparib did not enhance the p53 activation seen with the MDM2 inhibitors alone. These results demonstrate that the synergistic effect on growth inhibition observed in the combination between rucaparib and Nutlin-3/RG7388 is not the result of increased p53 molecular pathway activation. Nevertheless, combined treatment of Nutlin-3/RG7388 with rucaparib increased cell cycle arrest and apoptosis, which was marked for A2780 and IGROV-1. These data indicate that combination treatment with MDM2 inhibitors and rucaparib has synergistic and dose reduction potential for the treatment of ovarian cancer, dependent on cell type.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer

et al. 2017

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“…Growth inhibition by Nutlin-3/RG7388 was investigated using the sulforhodamine-B (SRB) assay for a panel of wild-type and mutant TP53 ovarian cancer cell lines derived from tumours of different histological subtypes [13–16] (Figure 1A and Table 1). The required concentration of each compound leading to 50% growth inhibition (GI 50 ) showed that wild-type TP53 ovarian cancer cell lines were significantly more sensitive to Nutlin-3/RG7388 compared to mutant, which is consistent with their mechanism of action ( p<0.0001 Mann-Whitney test).…”

Section: Resultsmentioning

confidence: 99%

Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer

2016

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Ovarian cancer is the fifth leading cause of cancer-related female deaths. Due to serious side effects, relapse and resistance to standard chemotherapy, better and more targeted approaches are required. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies, non-genotoxic activation of wild-type p53 by small molecule inhibition of the MDM2-p53 binding interaction is a promising therapeutic strategy. Proof of concept was established with the cis-imidazoline Nutlin-3, leading to the development of RG7388 and other compounds currently in early phase clinical trials. This preclinical study evaluated the effect of Nutlin-3 and RG7388 as single agents and in combination with cisplatin in a panel of ovarian cancer cell lines. Median-drug-effect analysis showed Nutlin-3 or RG7388 combination with cisplatin was additive to, or synergistic in a p53-dependent manner, resulting in increased p53 activation, cell cycle arrest and apoptosis, associated with increased p21WAF1 protein and/or caspase-3/7 activity compared to cisplatin alone. Although MDM2 inhibition activated the expression of p53-dependent DNA repair genes, the growth inhibitory and pro-apoptotic effects of p53 dominated the response. These data indicate that combination treatment with MDM2 inhibitors and cisplatin has synergistic potential for the treatment of ovarian cancer, dependent on cell genotype.

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“…As a further proof of the synthetic potential of this methodology, the arylation of a few interesting heteroarene molecular cores was tested (Scheme 3). For instance, menadione and its derivatives have been applied from anticancer treatments 18 to green chemistry. 19 As it is seen in Scheme 3a, menadione was derivatized in one step by method B in good yield.…”

Section: Scheme 2 Initial Experimentmentioning

confidence: 99%

Mild‐Base‐Promoted Arylation of (Hetero)Arenes with Anilines

Monzón

Santos

Pinacho-Crisóstomo

et al. 2018

Chemistry An Asian Journal

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Transition metal-free radical arylation of heteroarenes is achieved at room temperature by simply adding aqueous sodium carbonate to a solution of the corresponding heteroarene and arenediazonium salt, which can even be formed in situ. Such an easy, inexpensive and mild methodology has been optimized and applied to the expeditious modification of interesting molecular cores like naphthylimide or bisthienylcyclopentenes.

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Apatone ® induces endometrioid ovarian carcinoma (MDAH 2774) cells to undergo karyolysis and cell death by autoschizis: A potent and safe anticancer treatment

Cited by 5 publications

References 90 publications

Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer

Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer

Pre-clinical efficacy and synergistic potential of the MDM2-p53 antagonists, Nutlin-3 and RG7388, as single agents and in combined treatment with cisplatin in ovarian cancer

Mild‐Base‐Promoted Arylation of (Hetero)Arenes with Anilines

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