PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance

Tessoulin, Benoît; Descamps, Géraldine; Moreau, Philippe; Maïga, Sophie; Lodé, Laurence; Godon, Catherine; Marionneau-Lambot, Séverine; Oullier, Thibauld; Gouill, Steven Le; Amiot, Martine; Pellat‐Deceunynck, Catherine

doi:10.1182/blood-2014-01-548800

Cited by 146 publications

(171 citation statements)

References 40 publications

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“…Taken together, our findings suggest that PK11007 and other thiol-modifying compounds, such as PRIMA, MIRA, and STIMA, despite alkylating and stabilizing the p53 protein, exert their antitumor function not only via reactivating p53 but also via other cellular mechanisms, such as increase of cellular ROS to toxic levels and activation of the UPR (33). This finding would also explain the seemingly contradictory reports that PRIMA-1, MIRA-1, and STIMA-1 induce cell death also in cell lines with DNA contact mutants that cannot be rescued by simple protein stabilization (12,11,14).…”

Section: Discussionmentioning

confidence: 65%

“…The biological effects of APR-246 may not be directly dependent on the p53 status but rather on the perturbation of the intracellular GSH/ROS balance and the respective cellular context (31)(32)(33). To test whether PK11007 also increases ROS levels, we incubated NUGC-3, NUGC-4, HUH-6, HUH-7, and MKN1 cells with PK11007 for 2 h and stained the cells with CellROX Deep Red dye, which exhibits a strong fluorescent signal upon oxidation by ROS.…”

Section: Pk11007 Induces Ros Especially In Mutant P53mentioning

confidence: 99%

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2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

Bauer

Joerger

Fersht

2016

Proc. Natl. Acad. Sci. U.S.A.

100

113

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The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53’s oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1MET(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells.

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Section: Discussionmentioning

confidence: 65%

Section: Pk11007 Induces Ros Especially In Mutant P53mentioning

confidence: 99%

2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

Bauer

Joerger

Fersht

2016

Proc. Natl. Acad. Sci. U.S.A.

100

113

View full text Add to dashboard Cite

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“…However, several studies have suggested that APR-246 may also exert p53-independent effects. These include generating ROS,12 13 upregulating p7311 and suppressing c-Myc expression 11. Additionally, some investigators have even asserted that APR-246 may act entirely through p53-independent pathways in some tumour cells 11 12.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, recent studies have also suggested that APR-246 may exert additional effects through p53-independent mechanisms 11–13. These include generating reactive oxygen species (ROS) by antagonising the glutathione and thioredoxin reductase 1 pathway,12 13 activating p63, p73 and promyelocytic leukaemia tumour suppressor proteins,11 14 15 and suppressing the c-Myc oncogene 11…”

Section: Introductionmentioning

confidence: 99%

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma

Liu

Read

Cullinane

et al. 2015

Gut

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“…Downloaded by [University of Western Ontario] at 14:50 11 April 2015highlighting the significance of ROS production in PRIMA-1Met-induced cell death26 ; thus it would be interesting to analyze the oxidative stress pathways in PRIMA-1Met-treated WM cells in future studies.…”

mentioning

confidence: 99%

PRIMA-1Met induces apoptosis in Waldenström's Macroglobulinemia cells independent of p53

Sobhani

Abdi

Manujendra

et al. 2015

Cancer Biology & Therapy

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PRIMA-1Met has shown promising preclinical activity in various cancer types. However, its effect on Waldenström's Macroglobulinemia (WM) cells as well as its exact mechanism of action is still elusive. In this study, we evaluated the anti- tumor activity of PRIMA-1Met alone and in combination with dexamethasone or bortezomib in WM cell lines and primary samples. Treatment of WM cells with PRIMA-1Met resulted in induction of apoptosis, inhibition of migration and suppression of colony formation. Upon PRIMA-1Met treatment, p73 was upregulated and Bcl-xL was down-regulated while no significant change in expression of p53 was observed. Furthermore, siRNA knockdown of p53 in WM cell line did not influence the PRIMA-1Met-induced apoptotic response whereas silencing of p73 inhibited latter response in WM cells. Importantly, combined treatment of BCWM-1 cells with PRIMA-1Met and dexamethasone or bortezomib induced synergistic reduction in cell survival. Our study provides insights into the mechanisms of anti-WM activity of PRIMA-1Met and supports further clinical evaluation of PRIMA-1Met as a potential novel therapeutic intervention in WM.

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PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance

Abstract: Key Points• Myeloma cells are highly sensitive to PRIMA-1 Met , independent of p53.• PRIMA-1Met induces myeloma cell death by impairing GSH/ROS balance.The aim of this study was to assess the efficiency of p53 reactivation and induction of massive apoptosis (PRIMA-1

Cited by 146 publications

References 40 publications

2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma

PRIMA-1Met induces apoptosis in Waldenström's Macroglobulinemia cells independent of p53

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