Induction of apoptosis in Ehrlich ascites tumour cells via p53 activation by a novel small-molecule MDM2 inhibitor – LQFM030

Mota, Mariana Flávia da; Cortez, Alane Pereira; Benfica, Polyana Lopes; Rodrigues, Bruna dos Santos; Castro, Thalyta F.; Macedo, Larissa Matuda; Castro, Carlos H.; Lião, Luciano M.; Carvalho, Flávio Silva de; Romeiro, Luiz Antônio Soares; Menegatti, Ricardo; Verli, Hugo; Villavicencio, Bianca; Valadares, Marize Campos

doi:10.1111/jphp.12573

Cited by 7 publications

(2 citation statements)

References 59 publications

(146 reference statements)

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“…( 2015 ) and Mota et al. ( 2016 ), respectively. After treatment, K562 cells (1 × 10 6 cells/mL) were harvested by centrifugation, washed with cold PBS and resuspended with BD Cytofix/Cytoperm™ solution for 20 min at 4 °C.…”

Section: Methodsmentioning

confidence: 94%

4-Nerolidylcatechol: apoptosis by mitochondrial mechanisms with reduction in cyclin D1 at G0/G1 stage of the chronic myelogenous K562 cell line

Benfica

Ávila

Rodrigues

et al. 2017

Pharmaceutical Biology

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Context: 4-Nerolidylcatechol (4-NRC) has showed antitumor potential through apoptosis. However, its apoptotic mechanisms are still unclear, especially in leukemic cells.Objectives: To evaluate the cytotoxic potential of 4-NRC and its cell death pathways in p53-null K562 leukemic cells.Materials and methods: Cytotoxicity of 4-NRC (4.17–534.5 μM) over 24 h of exposure was evaluated by MTT assay. 4-NRC-induced apoptosis in K562 cells was investigated by phosphatidylserine (PS) externalization, cell cycle, sub-G1, mitochondrial evaluation, cytochrome c, cyclin D1 and intracellular reactive oxygen species (ROS) levels, and caspase activity analysis.Results: IC50 values obtained were 11.40, 27.31, 15.93 and 15.70 μM for lymphocytes, K562, HL-60 and Jurkat cells, respectively. In K562 cells, 4-NRC (27 μM) promoted apoptosis as verified by cellular morphological changes, a significant increase in PS externalization and sub-G1 cells. Moreover, it significantly arrested the cells at the G0/G1 phase due to a reduction in cyclin D1 expression. These effects of 4-NRC also significantly promoted a reduction in mitochondrial activity and membrane depolarization, accumulation of cytosolic cytochrome c and ROS overproduction. Additionally, it triggered an increase in caspases -3/7, -8 and -9 activities. When the cells were pretreated with N-acetyl-l-cysteine ROS scavenger, 4-NRC-induced apoptosis was partially blocked, which suggests that it exerts cytotoxicity though not exclusively through ROS-mediated mechanisms.Discussion and conclusion: 4-NRC has antileukemic properties, inducing apoptosis mediated by mitochondrial-dependent mechanisms with cyclin D1 inhibition. Given that emerging treatment concepts include novel combinations of well-known agents, 4-NRC could offer a promising alternative for chemotherapeutic combinations to maximize tumour suppression.

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Section: Methodsmentioning

confidence: 94%

4-Nerolidylcatechol: apoptosis by mitochondrial mechanisms with reduction in cyclin D1 at G0/G1 stage of the chronic myelogenous K562 cell line

Benfica

Ávila

Rodrigues

et al. 2017

Pharmaceutical Biology

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“…However, although known to significantly reduce ascites volume, none of these agents improved OS in clinical trials 36 . Regarding MDM2 inhibitors, previous studies reported that LQFM030 shows antitumor effects and an inhibitory effect on ascites production on Ehrlich ascites tumor cells derived from breast cancer 37,38 . Although the genetic and biological characteristics of CCCs are becoming clear, no single specific inhibitor has been shown to be sufficiently effective.…”

Section: Discussionmentioning

confidence: 99%

Effect of murine double‐minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys

et al. 2020

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Toxico-pharmacological evaluations of the small-molecule LQFM166: Inducer of apoptosis and MDM2 antagonist

Santos

Silva

Carvalho

et al. 2018

Chemico-Biological Interactions

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Induction of apoptosis in Ehrlich ascites tumour cells via p53 activation by a novel small-molecule MDM2 inhibitor – LQFM030

Abstract: These results suggest that the small-molecule p53 activator LQFM030 (2) has the potential for further development as a novel cancer therapeutic agent.

Cited by 7 publications

References 59 publications

4-Nerolidylcatechol: apoptosis by mitochondrial mechanisms with reduction in cyclin D1 at G0/G1 stage of the chronic myelogenous K562 cell line

4-Nerolidylcatechol: apoptosis by mitochondrial mechanisms with reduction in cyclin D1 at G0/G1 stage of the chronic myelogenous K562 cell line

Effect of murine double‐minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys

Toxico-pharmacological evaluations of the small-molecule LQFM166: Inducer of apoptosis and MDM2 antagonist

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