Piperlongumine (piplartine) and analogues: Antiproliferative microtubule-destabilising agents

Meegan, Mary J.; Nathwani, Seema M.; Twamley, Brendan; Zisterer, Daniela M.; O’Boyle, Niamh M.

doi:10.1016/j.ejmech.2016.09.048

Cited by 40 publications

(28 citation statements)

References 28 publications

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“…In order to evaluate whether 28 directly binds to tubulin at the colchicine binding site, we carried out a competition assay with N , N ′-ethylene-bis(iodoacetamide) (EBI) in MGC-803 cells as described in a previously published paper 47 . EBI was an alkylating agent that cross-links the Cys239 and the Cys354 residues of β -tubulin involved in the colchicine-binding site, forming a EBI: β -tubulin adduct 48 . The adduct was easily detectable by Western blot as a second immunoreactive β -tubulin band that migrated faster than β -tubulin itself 49 .…”

Section: Resultsmentioning

confidence: 99%

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Liu

et al. 2017

Sci Rep

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We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.

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Section: Resultsmentioning

confidence: 99%

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Liu

et al. 2017

Sci Rep

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“…Piplartine is a well characterizated cytotoxic agent, able to induce ROS selectively in different cancer cells, leading to cell death by apoptosis [ 3 – 18 ]. Many piplartine analogs have been synthesized and evaluated against cancer cells; however, this class of compounds has never been employed as ligand for composition of metal complexes.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have shown that complexes of ruthenium with different ligands can induce cytotoxic activity in micromolar or molar range against several cancer cell lines [ 44 – 46 ]. Moreover, piplartine is able to kill cancer cells of different histological types, including hematological, colon, melanocyte, lung, breast, central nervous system, pancreatic, nasopharyngeal, osseous, bladder, renal, and prostate in micromolar range [ 10 , 12 , 18 ]. In the present work, both piplartine-containing ruthenium complexes showed cytotoxic activity up to 12 fold higher than metal-free piplartine.…”

Section: Discussionmentioning

confidence: 99%

“…Piplartine (piperlongumine) is an alkaloid, which is found in some Piper species. We and along with other research groups have been investigating the anticancer potential of piplartine, and some antineoplastic characteristics have been assigned to this molecule, including potent cytotoxic, genotoxic, antitumor, antiangiogenic and antimetastatic properties, as well as attractive good bioavailability and safety [ 3 – 18 ]. Historically, much attention has been given to this molecule after its cytotoxicity and ability to induce the production of reactive oxygen species (ROS) selectively in cancer cells were published by Raj et al [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells

Irs

et al. 2017

Oncotarget

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Piplartine (piperlongumine) is a plant-derived molecule that has been receiving intense interest due to its anticancer characteristics that target the oxidative stress. In the present paper, two novel piplartine-containing ruthenium complexes [Ru(piplartine)(dppf)(bipy)](PF6)2 (1) and [Ru(piplartine)(dppb)(bipy)](PF6)2 (2) were synthesized and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes are more potent than metal-free piplartine in a panel of cancer cell lines on monolayer cultures, as well in 3D model of cancer multicellular spheroids formed from human colon carcinoma HCT116 cells. Mechanistic studies uncovered that the complexes reduced the cell growth and caused phosphatidylserine externalization, internucleosomal DNA fragmentation, caspase-3 activation and loss of the mitochondrial transmembrane potential on HCT116 cells. Moreover, the pre-treatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced the complexes-induced apoptosis, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. Treatment with the complexes also caused a marked increase in the production of reactive oxygen species (ROS), including hydrogen peroxide, superoxide anion and nitric oxide, and decreased reduced glutathione levels. Application of N-acetyl-cysteine, an antioxidant, reduced the ROS levels and apoptosis induced by the complexes, indicating activation of ROS-mediated apoptosis pathway. RNA transcripts of several genes, including gene related to the cell cycle, apoptosis and oxidative stress, were regulated under treatment. However, the complexes failed to induce DNA intercalation. In conclusion, the complexes are more potent than piplartine against different cancer cell lines and are able to induce caspase-dependent and mitochondrial intrinsic apoptosis on HCT116 cells by ROS-mediated pathway.

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“…Worth noting is the pellitorine (occurring in pellitory roots) has been shown to have strong cytotoxic activities against HL60 (Human promyelocytic leukemia strain) and MCT-7 (Brest cancer strain) cell lines, with IC50 values of 13.0 µg/mL and 1.8 µg/mL, respectively [43]. Piplartine and analogues have exhibited potent effects in human breast carcinoma MCF-7 cells, whilst being relatively non-toxic to non-tumorigenic MCF-10a cells [44,45]. Other alkamides, as capsaicin was reported to induce the apoptosis of prostate cancer cell lines [46], while pharnilatin did so for those of skin melanoma, as well as lung, ovary and colon [47].…”

Section: Discussionmentioning

confidence: 99%

Bioactivity-guided isolation of alkamides from a cytotoxic fraction of the ethyl acetate extract of Anacyclus pyrethrum (L.) DC. roots.

Hamimed

Boulebda

Laouer

et al. 2018

Current Issues in Pharmacy and Medical Sciences

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Introduction. The alcohol extract of Pellitory (Anacyclus pyrethrum) roots has been previously shown to exert anticancer activities on the Human Colorectal Cancer Cell Line (HCT) by targeting apoptosis, metastasis and cell cycle arrest. However, the nature of the cytotoxic molecules associated with this activity remains unexplored. Aims. This study aims to reinvestigate Pellitory root extract as regard to its cytotoxic activity and to proceed to a bioguided fractionation to explore its active fraction and to give new insight in their phytochemical constituents. Methods. Powdered roots were subjected to repeated extraction with Petroleum ether (Pe), Chloroform (Ch), Ethyl acetate (Ea) and Methanol (Me). Pellitory extracts were then screened for cytotoxic activity using the Brine Shrimp Lethality (BSL) bioassay. Results. Ea extract exhibited a marked cytotoxic activity, with LC50 of 249.26 μg/mL in the BSL bioassay. The remaining extracts (Pe,Ch,Me) treated groups exhibited no or low mortality in the range of tested concentrations (1-1000 µg/mL). BSL assay-guided chromatographic fractionation of Ea active Extract revealed a highly cytotoxic fraction (F11) with LC50 of 42.5 µg/mL. Multistep purifications of the active F11 fraction afforded four alkamides, namely N-isobutyldeca-2,4-dienamide or Pellitorine (I), N-propyldodeca- -2,8-dienamide (II), N-isobutyltetradeca-2,4-dienamide (III) and N-propylnona-2,5- -dienamide (IV). Conclusions. This study suggests that cytotoxic activity is localized mainly in the ethyl acetate extract (Ea) of pellitory roots. BSL assay fractionation of this active extract leads to the isolation of four alkamides, including pellitorine (I). While this isobutyl alkamide has previously shown strong cytotoxic activities against human cancer cell lines, the other compounds (II to IV) were not previously reported as cytotoxic. Subsequently, the isolated alkamides will be considered in future study as candidates for in depth in-vitro evaluation of their cytotoxicity against cancer and normal cell lines. Finally, through this study, BSL assay demonstrate again its usefulness as bench-top assay in exploring plant extracts for cytotoxic compounds.

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Piperlongumine (piplartine) and analogues: Antiproliferative microtubule-destabilising agents

Cited by 40 publications

References 28 publications

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells

Bioactivity-guided isolation of alkamides from a cytotoxic fraction of the ethyl acetate extract of Anacyclus pyrethrum (L.) DC. roots.

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