Design, synthesis and biological evaluation of new pyrrolidine carboxamide analogues as potential chemotherapeutic agents for hepatocellular carcinoma

Omar, Hany A.; Zaher, Dana M.; Srinivasulu, Vunnam; Hersi, Fatema; Tarazi, Hamadeh; Al‐Tel, Taleb H.

doi:10.1016/j.ejmech.2017.08.054

Cited by 18 publications

(9 citation statements)

References 38 publications

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“…The assay was performed as detailed before 53 . The monolayer culture of seeded HCC cells was scraped with a sterile micropipette tip to form a gap of a constant width.…”

Section: Methodsmentioning

confidence: 99%

Antrodia cinnamomea boosts the anti-tumor activity of sorafenib in xenograft models of human hepatocellular carcinoma

Chen

Omar

et al. 2018

Sci Rep

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Hepatocellular carcinoma (HCC) has been recognized worldwide as one of the major causes of cancer death. The medicinal fungus Antrodia cinnamomea (A. cinnamomea) has been served as a functional food for liver protection. The aim of the present study was to investigate the potential activity of A. cinnamomea extracts as a safe booster for the anticancer activity of sorafenib, a multi-kinase inhibitor approved for the treatment of HCC. The biologically active triterpenoids in the ethanolic extracts of A. cinnamomea (EAC) were initially identified by HPLC/LC/MS then the different extracts and sorafenib were assessed in vitro and in vivo. EAC could effectively sensitize HCC cells to low doses of sorafenib, which was perceived via the ability of the combination to repress cell viability and to induce cell cycle arrest and apoptosis in HCC cells. The ability of EAC to enhance sorafenib activity was mediated through targeting mitogen-activated protein (MAP) kinases, modulating cyclin proteins expression and inhibiting cancer cell invasion. Moreover, the proposed combination significantly suppressed ectopic tumor growth in mice with high safety margins compared to single-agent treatment. Thus, this study highlights the advantage of combining EAC with sorafenib as a potential adjuvant therapeutic strategy against HCC.

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“…The assay was performed as detailed before 53 . The monolayer culture of seeded HCC cells was scraped with a sterile micropipette tip to form a gap of a constant width.…”

Section: Methodsmentioning

confidence: 99%

Antrodia cinnamomea boosts the anti-tumor activity of sorafenib in xenograft models of human hepatocellular carcinoma

Chen

Omar

et al. 2018

Sci Rep

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“…We demonstrated that the tested compound significantly suppressed the proliferation of both tumor cell lines, with higher sensitivity in Caco-2, potentially because HCT116 is more resistant to many anticancer agents [32]. Some studies have shown that G1/S or G2/M phase cell cycle arrest can mediate pyrrolidine derivates' cytotoxic effects [18,33]. Flow cytometric analysis was used to determine whether SS13 induced changes in the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

“…in the Red Sea, and Aegyptolidines A and B, from the fungus Aspergillus aegyptiacus [15], are known for their cytotoxic activity against several tumor cell lines [16]. The cytotoxic effects of pyrrolidine derivatives are exerted through various mechanisms, including cell cycle arrest [17,18], the induction of apoptosis and the modulation of various signaling pathways, among others [19,20]. Tumor cells exhibit high migration rates, leading to invasion and metastasis.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of Both Extrinsic and Intrinsic Apoptotic Pathways in Tridecylpyrrolidine-Diol Derivative-Induced Apoptosis In Vitro

Nosálová

Kešeľáková

Kello

et al. 2023

IJMS

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Despite the decreasing trend in mortality from colorectal cancer, this disease still remains the third most common cause of death from cancer. In the present study, we investigated the antiproliferative and pro-apoptotic effects of (2S,3S,4R)-2-tridecylpyrrolidine-3,4-diol hydrochloride on colon cancer cells (Caco-2 and HCT116). The antiproliferative effect and IC50 values were determined by the MTT and BrdU assays. Flow cytometry, qRT-PCR and Western blot were used to study the cellular and molecular mechanisms involved in the induction of apoptotic pathways. Colon cancer cell migration was monitored by the scratch assay. Concentration-dependent cytotoxic and antiproliferative effects on both cell lines, with IC50 values of 3.2 ± 0.1 μmol/L (MTT) vs. 6.46 ± 2.84 μmol/L (BrdU) for HCT116 and 2.17 ± 1.5 μmol/L (MTT) vs. 1.59 ± 0.72 μmol/L (BrdU), for Caco-2 were observed. The results showed that tridecylpyrrolidine-induced apoptosis was associated with the externalization of phosphatidylserine, reduced mitochondrial membrane potential (MMP) accompanied by the activation of casp-3/7, the cleavage of PARP and casp-8, the overexpression of TNF-α and FasL and the dysregulation of Bcl-2 family proteins. Inhibition of the migration of treated cells across the wound area was detected. Taken together, our data show that the anticancer effects of tridecylpyrrolidine analogues in colon cancer cells are mediated by antiproliferative activity, the induction of both extrinsic and intrinsic apoptotic pathways and the inhibition of cell migration.

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“…This mechanism was validated by the drug’s ability to enhance the phosphorylation of ataxia telangiectasia-mutated (ATM) or ATM-Rad3-related kinases (ATR) as well as the phosphorylation of Ser139 residues on specialized γ-H2AX histones [ 11 ]. Importantly, the downregulation of cancer survival proteins remains a challenge in developing new cancer treatment approaches [ 12 , 13 ]. Several reports indicated that targeting pro-apoptotic and anti-apoptotic signaling pathways in cancers along with multiple key enzymes required for cancer survival and spread, such as TrxR, GSHR, inositol-3-phosphate synthase, phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and a Ras/extracellular kinase regulated by signaling (ERK), represent a unique approach that disrupts the evolutionary dynamics of the cancer ecosystem [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways

Zaher

Ramadan

El‐Awady

et al. 2021

Cancers

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(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer.

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Design, synthesis and biological evaluation of new pyrrolidine carboxamide analogues as potential chemotherapeutic agents for hepatocellular carcinoma

Cited by 18 publications

References 38 publications

Antrodia cinnamomea boosts the anti-tumor activity of sorafenib in xenograft models of human hepatocellular carcinoma

Antrodia cinnamomea boosts the anti-tumor activity of sorafenib in xenograft models of human hepatocellular carcinoma

Involvement of Both Extrinsic and Intrinsic Apoptotic Pathways in Tridecylpyrrolidine-Diol Derivative-Induced Apoptosis In Vitro

A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways

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