Trans-chalcone increases p53 activity via DNAJB1/HSP40 induction and CRM1 inhibition

Silva, Gabriel; Marins, Mozart; Chaichanasak, Nadda; Yoon, Yongdae; Fachin, Ana Lúcia; Pinhanelli, Vitor Caressato; Regasini, Luís Octávio; Santos, Mariana Bastos dos; Ayusso, Gabriela Miranda; Marques, Beatriz de Carvalho; Wu, Wells W.; Phue, Je-Nie; Shen, Rong-Fong; Baek, Seung Joon

doi:10.1371/journal.pone.0202263

Cited by 19 publications

(21 citation statements)

References 44 publications

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“…In previous studies conducted by our group, chalcone with unsubstituted rings A and B had potent antiproliferative and proapoptotic activities 18 . However, its low solubility in water enables limited additional pharmacological assays, mainly in vivo experiments.…”

Section: Antiproliferative Activity Of Chalcones 1-20mentioning

confidence: 83%

“…Iftikhar et al reported that chalcone bearing chlorine at position 2 was effective against breast cancer cells (CAL-51 line) and induced accumulation of p53 protein 17 . Silva and coauthors described unsubstituted chalcone increased p53 protein activity in osteosarcoma cells (U2OS line) through the induction of heat shock protein DNAJB1 18 .…”

Section: Introductionmentioning

confidence: 99%

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Antiproliferative activity and p53 upregulation effects of chalcones on human breast cancer cells

Santos

Anselmo

Oliveira

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Chalcones are valuable structures for drug discovery due to their broad bioactivity spectrum. In this study, we evaluated 20 synthetic chalcones against estrogen-receptor-positive breast cancer cells (MCF-7 line) and triple-negative breast cancer (TNBC) cells (MDA-MB-231 line). Antiproliferative screening by MTT assay resulted in two most active compounds: 2-fluoro-4'-aminochalcone (11) and 3-pyridyl-4'-aminochalcone (17). Their IC 50 values ranged from 13.2 to 34.7 mM against both cell lines. Selected chalcones are weak basic compounds and maintained their antiproliferative activity under acidosis conditions (pH 6.7), indicating their resistance to ion-trapping effect. The mode of breast cancer cells death was investigated and chalcones 11 and 17 were able to induce apoptosis rather than necrosis in both lines. Antiproliferative target investigations with MCF-7 cells suggested 11 and 17 upregulated p53 protein expression and did not affect Sp1 protein expression. Future studies on chalcones 11 and 17 can define their in vivo therapeutic potential.

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Section: Antiproliferative Activity Of Chalcones 1-20mentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Antiproliferative activity and p53 upregulation effects of chalcones on human breast cancer cells

Santos

Anselmo

Oliveira

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…However, Dos et al reported that series of chalcones with halogens on ring B and additional benzene rings ( 47 IC 50 : 13.2–34.7 μM, Figure 11 ) showed antiproliferative activity against breast cancer cells (MCF-7 and MDA-MB-231), with upregulation of p53 and showed no effect on Sp1 protein expression [ 129 ]. Further mechanistic studies demonstrated that TChal could bind and degrade chromosome region maintenance 1 (CRM1), a nuclear export receptor involved in the active transport of tumor suppressors, and increase heat-shock protein 40 (HSP40) expression in U2OS osteosarcoma cells; the interaction of HSP40 with MDM2 blocked MDM2-mediated ubiquitination of p53, leading to the enhanced stability and activation of p53 [ 128 , 130 ]. Moreover, Siqueira et al reported that TChal could reestablish the p53 pathway and prevent the overexpression of Wnt/β-catenin tumor development, inducing autophagy-related cell death and decreasing the metastatic capacity of HCC HuH7.5 cells [ 131 ].…”

Section: Representative Mechanisms Of Anticancer Action Of Chalconesmentioning

confidence: 99%

Chalcone Derivatives: Role in Anticancer Therapy

et al. 2021

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Chalcones (1,3-diaryl-2-propen-1-ones) are precursors for flavonoids and isoflavonoids, which are common simple chemical scaffolds found in many naturally occurring compounds. Many chalcone derivatives were also prepared due to their convenient synthesis. Chalcones as weandhetic analogues have attracted much interest due to their broad biological activities with clinical potentials against various diseases, particularly for antitumor activity. The chalcone family has demonstrated potential in vitro and in vivo activity against cancers via multiple mechanisms, including cell cycle disruption, autophagy regulation, apoptosis induction, and immunomodulatory and inflammatory mediators. It represents a promising strategy to develop chalcones as novel anticancer agents. In addition, the combination of chalcones and other therapies is expected to be an effective way to improve anticancer therapeutic efficacy. However, despite the encouraging results for their response to cancers observed in clinical studies, a full description of toxicity is required for their clinical use as safe drugs for the treatment of cancer. In this review, we will summarize the recent advances of the chalcone family as potential anticancer agents and the mechanisms of action. Besides, future applications and scope of the chalcone family toward the treatment and prevention of cancer are brought out.

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“…However, in a phase I clinical trial LMB was found to have severe toxicities and therefore its clinical use was discarded (Newlands et al 1996 ). Other inhibitors such as the aromatic ketone Trans-chalcone (Silva et al 2018 ) and CBS9106 (Sakakibara et al 2011 ) were developed, but none of these candidates reached clinical practice so far.…”

Section: Discussionmentioning

confidence: 99%

Selinexor decreases HIF-1α via inhibition of CRM1 in human osteosarcoma and hepatoma cells associated with an increased radiosensitivity

Fallois

Kosyna

Mandl

et al. 2021

J Cancer Res Clin Oncol

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Background The nuclear pore complexes (NPCs) are built of about 30 different nucleoporins and act as key regulators of molecular traffic between the cytoplasm and the nucleus for sizeable proteins (> 40 kDa) which must enter the nucleus. Various nuclear transport receptors are involved in import and export processes of proteins through the nuclear pores. The most prominent nuclear export receptor is chromosome region maintenance 1 (CRM1), also known as exportin 1 (XPO1). One of its cargo proteins is the prolyl hydroxylase 2 (PHD2) which is involved in the initiation of the degradation of hypoxia-inducible factors (HIFs) under normoxia. HIFs are proteins that regulate the cellular adaptation under hypoxic conditions. They are involved in many aspects of cell viability and play an important role in the hypoxic microenvironment of cancer. In cancer, CRM1 is often overexpressed thus being a putative target for the development of new cancer therapies. The newly FDA-approved pharmaceutical Selinexor (KPT-330) selectively inhibits nuclear export via CRM1 and is currently tested in additional Phase-III clinical trials. In this study, we investigated the effect of CRM1 inhibition on the subcellular localization of HIF-1α and radiosensitivity. Methods Human hepatoma cells Hep3B and human osteosarcoma cells U2OS were treated with Selinexor. Intranuclear concentration of HIF-1α protein was measured using immunoblot analysis. Furthermore, cells were irradiated with 2–8 Gy after treatment with Selinexor compared to untreated controls. Results Selinexor significantly reduced the intranuclear level of HIF-1α protein in human hepatoma cells Hep3B and human osteosarcoma cells U2OS. Moreover, we demonstrated by clonogenic survival assays that Selinexor leads to dose-dependent radiosensitization in Hep3B-hepatoma and U2OS-osteosarcoma cells. Conclusion Targeting the HIF pathway by Selinexor might be an attractive tool to overcome hypoxia-induced radioresistance.

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Trans-chalcone increases p53 activity via DNAJB1/HSP40 induction and CRM1 inhibition

Cited by 19 publications

References 44 publications

Antiproliferative activity and p53 upregulation effects of chalcones on human breast cancer cells

Antiproliferative activity and p53 upregulation effects of chalcones on human breast cancer cells

Chalcone Derivatives: Role in Anticancer Therapy

Selinexor decreases HIF-1α via inhibition of CRM1 in human osteosarcoma and hepatoma cells associated with an increased radiosensitivity

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