Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer

Fransson, Åsa; Glaessgen, Daria; Alfredsson, Jessica; Wiman, Klas G.; Bajalica‐Lagercrantz, Svetlana; Mohell, Nina

doi:10.1186/s13048-016-0239-6

Cited by 56 publications

(50 citation statements)

References 37 publications

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“…The combination index (C.I.) has been calculated by means of the following equation [41]: %PCV = % Predicted Cell Viability = % Cell Viability Drug1 x % Cell Viability Drug2 x 0.01. CI = Combination Index = % Measured Cell Viability Drug1 + Drug2 / %PCV.…”

Section: Discussionmentioning

confidence: 99%

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

Catalogna

Talarico

Dattilo

et al. 2017

Cell Physiol Biochem

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Background/Aims: The importance of copper in the metabolism of cancer cells has been widely studied in the last 20 years and a clear-cut association between copper levels and cancer deregulation has been established. Copper-64, emitting positrons and β-radiations, is indicated for the labeling of a large number of molecules suitable for radionuclide imaging as well as radionuclide therapy. Glioblastoma multiforme (GBM) is the CNS tumor with the worse prognosis, characterized by high number of recurrences and strong resistance to chemo-radio therapy, strongly affecting patients survival. We have recently discovered and studied the small molecule SI113, as inhibitor of SGK1, a serine/threonine protein kinase, that affects several neoplastic phenotypes and signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation, perturbs cell cycle progression and restores chemoradio sensibility by modulating SGK1-related substrates. In the present paper we aim to characterize the combined effects of 64 CuCl 2 and SI113 on human GBM cell lines with variable p53 expression. Methods: Cell viability, cell death and stress/authopagic related pathways were then analyzed by FACS and WB-based assays, after exposure to SI113 and/or 64 CuCl 2 . Results: We demonstrate here, that i) 64 CuCl 2 is able to induce a time and dose dependent modulation of cell viability (with different IC 50 values) in highly malignant gliomas and that the co-treatment with SI113 leads to ii) additive/synergistic effects in terms of cell death; iii) enhancement of the effects of ionizing radiations, probably by a TRC1 modulation; iv) modulation of the autophagic response. Conclusions: Evidence reported here underlines the therapeutic potential of the combined treatment with SI113 and 64 CuCl 2 in GBM cells.G. Catalogna and C. Talarico equally contributed to this work.

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Section: Discussionmentioning

confidence: 99%

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

Catalogna

Talarico

Dattilo

et al. 2017

Cell Physiol Biochem

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“…Since many chemotherapy drugs depend on wild-type p53 for induction of tumor cell apoptosis, the restoration of wild-type p53 by APR-246 has the potential to sensitize p53-mutant cancers to these drugs. Indeed, APR-246 has showed strong synergy with traditional chemotherapy drugs such as cisplatin, 5-fluorouracil and doxorubicin in multiple p53-mutant expressing ovarian cancers (52). Furthermore, mutant p53 targeting with APR-246 effectively eliminates resistance to the proteasome inhibitor carfilzomib (53).…”

Section: Compounds That Directly Target Mutant P53mentioning

confidence: 99%

Molecularly targeted therapies for p53-mutant cancers

Zhao

Tahaney

Mazumdar

et al. 2017

Cell. Mol. Life Sci.

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The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.

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“…Theoretically, at least half of all cancer patients would benefit from strategies targeting p53. Also, the combination of mutp53 reactivators and traditional anticancer drugs may exhibit synergetic effects, as conventional anticancer drugs usually depend on an intact p53 pathway (Deben et al, ; Fransson et al, ), which expands the application of mutp53 reactivators. Encouragingly, some of the mutp53 reactivators are in clinical trials; PRIMA‐1 Met (APR‐246) and COTI‐2 showed positive results (Deneberg et al, ).…”

Section: Discussionmentioning

confidence: 99%

Salvation of the fallen angel: Reactivating mutant p53

Yang

Wang

Chen

et al. 2019

British J Pharmacology

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The transcription factor p53 is known as the guardian of the genome for its powerful anti-tumour capacity. However, mutations of p53 that undermine their protein structure, resulting in loss of tumour suppressor function and gain of oncogenic function, have been implicated in more than half of human cancers. The crucial role of mutant forms of p53 in cancer makes it an attractive therapeutic target. A large number of candidates, including low MW compounds, peptides, and nucleic acids, have been identified or designed to rescue p53 mutants and reactivate their anti-tumour capacity through a variety of mechanisms. In this review, we summarize the progress made in the reactivation of mutant forms of p53, focusing on the pharmacological mechanisms of the reactivators of p53 mutants.

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Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer

Cited by 56 publications

References 37 publications

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

Molecularly targeted therapies for p53-mutant cancers

Salvation of the fallen angel: Reactivating mutant p53

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