scholarly journals A New Hybrid δ-Lactone Induces Apoptosis and Potentiates Anticancer Activity of Taxol in HL-60 Human Leukemia Cells

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1479 ◽  
Author(s):  
Katarzyna Gach-Janczak ◽  
Joanna Drogosz-Stachowicz ◽  
Angelika Długosz-Pokorska ◽  
Rafał Jakubowski ◽  
Tomasz Janecki ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Anticancer Agents ◽  
Biologically Active ◽  
Human Leukemia ◽  
Apoptosis Induction ◽  
Hybrid Compound ◽  
Drug Candidates ◽  
Natural Substances ◽  
High Cytotoxic Activity ◽  
Induced Apoptosis

In the search for new drug candidates, researchers turn to natural substances isolated from plants which may be either used directly or may serve as a source for chemical modifications. An interesting strategy in the design of novel anticancer agents is based on the conjugation of two or more biologically active structural motifs into one hybrid compound. In this study, we investigated the anticancer potential of 4-benzyl-5,7-dimethoxy-4-methyl-3-methylidene-3,4-dihydro-2H-chroman-2-one (DL-247), a new hybrid molecule combining a chroman-2-one skeleton with an exo-methylidene bond conjugated with a carbonyl group, in human myeloid leukemia HL-60 cell line. The cytotoxicity of the new compound was tested using MTT assay. The effect of DL-247 on cell proliferation and apoptosis induction were studied by flow cytometry, fluorometric assay and ELISA analysis. DL-247 displayed high cytotoxic activity (IC50 = 1.15 µM, after 24 h incubation), significantly inhibited cell proliferation and induced apoptosis by both, the intrinsic and extrinsic pathways. A combination of DL-247 with taxol exhibited a strong synergistic effect on DNA damage generation, apoptosis induction and inhibition of cell growth.

scholarly journals Synthesis of 2,2,6-Trisubstituted 5-Methylidene-tetrahydropyran-4-ones with Anticancer Activity

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 611
Author(s):  
Tomasz Bartosik ◽  
Jacek Kędzia ◽  
Joanna Drogosz-Stachowicz ◽  
Anna Janecka ◽  
Urszula Krajewska ◽  
...  
Keyword(s):  
Anticancer Drug ◽  
Biological Evaluation ◽  
Human Leukemia ◽  
Reaction Sequence ◽  
Drug Candidates ◽  
Michael Adducts ◽  
M Phase ◽  
High Cytotoxic Activity ◽  
Induced Apoptosis ◽  
Very High

In our continuous search for new, relatively simple 2-alkylidene-1-oxoheterocycles as promising anticancer drug candidates, herein we report an efficient synthesis of 2,2,6-trisubstituted 5-methylidenetetrahydropyran-4-ones. These compounds were obtained in a four step reaction sequence, in which starting diethyl 2-oxopropylphosphonate was transformed into 2,2-disubstituted 5-diethoxyphosphoryldihydropyran-4-ones, followed by Michael addition of various Grignard reagents and Horner-Wadsworth-Emmons reaction of the obtained adducts with formaldehyde. Stereochemistry of the intermediate Michael adducts is also discussed. Final 5-methylidenetetrahydropyran-4-ones were tested for their possible antiproliferative effect against three cancer cell lines and 6-isopropyl-2,2-dimethyl-5-methylidenetetrahydropyran-4-one (11c), which showed very high cytotoxic activity against HL-60 human leukemia cells and was three times more active than known anticancer drug carboplatin, was selected for further biological evaluation, in order to disclose its mechanism of action. The obtained results indicated that 11c induced apoptosis in HL-60 cells and caused the arrest of the cell cycle in the G2/M phase, which may suggest its cytotoxic and cytostatic activity.

Synthesis and anticancer activity of some pyrido[2,3-d]pyrimidine derivatives as apoptosis inducers and cyclin-dependent kinase inhibitors

2019 ◽  
Vol 11 (18) ◽  
pp. 2395-2414 ◽  
Author(s):  
Safinaz E-S Abbas ◽  
Riham F George ◽  
Eman M Samir ◽  
Mostafa MA Aref ◽  
Hatem A Abdel-Aziz
Keyword(s):  
Cell Cycle ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Cytotoxic Agents ◽  
Cyclin Dependent Kinase ◽  
Apoptosis Induction ◽  
Pyrimidine Derivatives ◽  
Induced Apoptosis ◽  
Emergence Of Resistance ◽  
Mcf 7

Aim: Due to emergence of resistance to available anticancer agents, there is a need to search for new cytotoxic agents. Methods: Pyrido[2,3- d]pyrimidines (4–6) and their tricyclic derivatives (7–13) were prepared and screened for their cytotoxicity against breast MCF-7, prostate PC-3 and lung A-549 cancer cell lines as well as normal fibroblasts WI-38. Results: The most active compounds were 6b, 6e and 8d compared with doxorubicin. Moreover, compounds 6b and 8d induced apoptosis in PC-3 and MCF-7, respectively via activation of CASP3 (in PC-3 only), Bax, p53 and down regulation of Bcl2 in addition to CDK4/6 inhibition. Conclusion: Pyrido[2,3- d]pyrimidine represents an important core for discovery of new potent cytotoxic agents acting on the cell cycle via apoptosis induction through either intrinsic or extrinsic pathways.

Purified Photoproducts of Merocyanine 540 Trigger Cytochrome C Release and Caspase 8-Dependent Apoptosis in Human Leukemia and Melanoma Cells

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4096-4108 ◽  
Author(s):  
Shazib Pervaiz ◽  
Mohamed A. Seyed ◽  
Jayshreekumari L. Hirpara ◽  
Marie-Véronique Clément ◽  
Kok W. Loh
Keyword(s):  
Cytochrome C ◽  
Anticancer Agents ◽  
Mitochondrial Permeability Transition ◽  
Melanoma Cells ◽  
Biologically Active ◽  
Rat Liver Mitochondria ◽  
Caspase 8 ◽  
Human Leukemia ◽  
Cytochrome C Release ◽  
Merocyanine 540

Abstract If the interplay between caspase proteases and mitochondria decide the fate of the cell during apoptosis, they may constitute useful molecular targets for novel drug design. We have shown that photoactivated merocyanine 540 (pMC540) triggers caspase-mediated apoptosis in HL60 leukemia and M14 melanoma cells. Because pMC540 is a mixture of photoproducts, we set out to purify the biologically active component(s) from this mixture and to investigate their ability to directly activate intracellular caspases and/or trigger mitochondrial events associated with apoptosis. Two photoproducts, namely C1 and C2, purified and characterized by mass spectroscopy and nuclear magnetic resonance (NMR) analysis, effectively induced apoptosis in HL60 and M14 cells. Interestingly, both C1 and C2 induced non–receptor-dependent activation of caspase 8, which was responsible for the downstream activation of caspase 3 and cell death. Both compounds induced the release of cytochrome C from mitochondria of tumor cells and from purified rat liver mitochondria; however, different mechanisms were operative in cytochrome C translocation in response to C1 or C2. C1-induced cytochrome C release was mediated by the mitochondrial permeability transition (MPT) pore and accompanied by a decrease in mitochondrial transmembrane potential (▵ψm), whereas cytochrome C release in response to C2 was independent of MPT pore opening. These findings do not exclude the possibility that changes in mitochondrial ▵ψm are critical for apoptosis in some instances, but support the notion that this may not be a universal step in the apoptotic process. Thus, identification of two novel anticancer agents that directly activate effector components of the apoptotic pathway could have potential implications for the development of newer chemotherapeutic drugs.

Novel Stilbene-Based Antileukemic Agents Active in P-Glycoprotein Expressing and Apoptosis-Resistant Acute Leukaemia Cell Lines.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4436-4436
Author(s):  
Stefania Grimaudo ◽  
Antonietta Di Cristina ◽  
Vincenzo Abbadessa ◽  
Simoni Daniele ◽  
Marinella Roberti ◽  
...  
Keyword(s):  
Cell Lines ◽  
Anticancer Agents ◽  
Acute Leukaemia ◽  
Phenyl Ring ◽  
Malignant Tumors ◽  
Biologically Active ◽  
Monocytic Differentiation ◽  
Leukaemia Cell ◽  
P Glycoprotein ◽  
Induced Apoptosis

Abstract The stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds and in accordance with Evans’ definition it can be considered as a privileged structure. One of the most relevant and studied stilbenes is Resveratrol, a phytoalexin present in grapes, endowed with chemopreventive and chemotherapeutic properties and able to induce apoptosis in different cancer cell lines. Since reduced apoptosis has been implicated in the development and progression of malignant tumors and in the occurrence of chemoresistant phenotypes, resveratrol-induced apoptosis might therefore contribute to its antitumor activity. However, resveratrol is a not potent cytotoxic compound if compared with others chemotherapeutic drugs and it is scarcely active in P-glycoprotein expressing (MDR) and Bcr-Abl expressing leukaemia cells. With the aim to find new stilbene compounds active in resistant leukaemia cells we synthesized a small library of resveratrol analogs, bearing the 3,5-dimethoxy motif at the A phenyl ring and amino, methoxy and hydroxy moieties at the 3′-and/or 4′-positions. Moreover, we synthesized analogues which incorporate a phenyl ring as bioisosteric substitution of the alkenyl bridge. Among these new stilbenes we identified two compounds endowed with interesting antileukemic properties: a) a methoxylated cis derivative active at nanomolar concentrations in P-glycoprotein expressing HL60-R and CEM VBL100 acute leukaemia cell lines and in P-glycoprotein and Bcr-Abl expressing K562-ADR cell line which is resistant to apoptosis induced by most common anticancer agents, and b) a terphenyl derivative active in MDR and Bcr-Abl expressing cell lines. Both compounds induced apoptosis prevalently through the mitochondrial pathway. Differently from resveratrol and other stilbenes, the therphenyl derivative induced a block of cells in G0-G1 phase of cell cycle which was associated to the shift of the phosphorylation state of pRb from hyperphosphorylated to hypophosphorylated. Morover, low concentrations of this compound were able to induced a potent granulocytic and monocytic differentiation of HL60 cells.

Berbamine-Induced Apoptosis in Human Leukemia K562 Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4234-4234
Author(s):  
Xiaoying Zhao ◽  
Lei Xu ◽  
Dong Wu ◽  
Rongzhen Xu
Keyword(s):  
Flow Cytometry ◽  
Cell Proliferation ◽  
Caspase 3 ◽  
K562 Cells ◽  
Human Leukemia ◽  
Dependent Manner ◽  
Flow Cytometry Assay ◽  
Transcript Levels ◽  
Induced Apoptosis ◽  
Dose Dependent

Abstract Purpose: To investigate apoptosis-inducing effects of Berbamine on human leukemia cells and to explore the underlying mechanism. Materials and methods: Berbamine was dissolved in 0.9% sodium chloride to an initial concentration of 1mg/ml and subsequently diluted to desired concentrations with cell culture medium. MTT was used to examine the effect of Berbamine on cell proliferation of K562 cells. Characteristic cellular morphological changes were used as indicators of apoptosis in K562 cells while the rate of apoptosis was measured by flow cytometry assay. Expression levels of apoptosis related genes bcl-2 and bax were determined by RT-PCR and the levels of bcr/abl were evaluated by nested-PCR. Levels of Caspase 3 were measured by flow cytometry assay. Results: Berbamine inhibited the cell proliferation significantly and in a dose-dependent manner in tested K562 cells. Its IC50 value was 5.23ug/ml. As determined by morphological observations and flow cytometry assay, Berbamine was able to induce apoptosis of K562 cells within 6 hours. The apoptosis rate of K562 was also dose-dependent. Steady-state transcript levels of bcr/abl decreased dramatically (half-quantity ratio from 1.284 to 0.506 within 72 hours following 8mg/ml Berbamine treatment. On the other hand, the protein levels of Caspase 3 surged from 18.36% to 38.25% (p<0.001) within 24 hours after treatment of 12mg/ml Berbamine. During the same period, no changes of bcl-2 or bax transcript levels were detected in the cells that were treated with 8mg/ml Berbamine. Conclusions: Our results suggest that Berbamine is a potent inhibitor of cell proliferation and a strong inducer of apoptosis in human K562 cells. The Berbamine-induced apoptosis pathway involves down regulation of bcr/abl and up regulation of Caspase 3 expressions. Neither bcl-2 nor bax plays substantial roles in Berbamine-induced K562 cell apoptosis.

scholarly journals Synthesis and Biological Evaluation of New Glycoconjugated LDH Inhibitors as Anticancer Agents

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3520 ◽  
Author(s):  
Felicia D’Andrea ◽  
Giulia Vagelli ◽  
Carlotta Granchi ◽  
Lorenzo Guazzelli ◽  
Tiziano Tuccinardi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Anticancer Agents ◽  
Biological Response ◽  
Biological Evaluation ◽  
Biologically Active ◽  
Cancer Cell Proliferation ◽  
Structural Variations ◽  
Lactate Formation ◽  
Synthesis And Biological Evaluation ◽  
Sugar Stereochemistry

Conjugation of known biologically active molecules to carbohydrate frameworks represents a valuable option for the preparation of hybrid, structurally-related families of compounds with the aim of modulating their biological response. Therefore, we present here a study on the preparation of d-galacto, d-manno, d-gluco, and d-lactose glycoconjugates of an established N-hydroxyindole-based (NHI) inhibitor of lactated dehydrogenase (LDH). Structural variations involved the sugar stereochemistry and size as well as the anchoring point of the NHI on the carbohydrate frame (either C-1 or C-6). In the case of the galactose anomeric glycoconjugate (C-1), intriguing solvent-dependent effects were observed in the glycosylation stereochemical outcome. The biological activity of the deprotected glycoconjugates in contrasting lactate formation and cancer cell proliferation are described.

Purified Photoproducts of Merocyanine 540 Trigger Cytochrome C Release and Caspase 8-Dependent Apoptosis in Human Leukemia and Melanoma Cells

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4096-4108 ◽  
Author(s):  
Shazib Pervaiz ◽  
Mohamed A. Seyed ◽  
Jayshreekumari L. Hirpara ◽  
Marie-Véronique Clément ◽  
Kok W. Loh
Keyword(s):  
Cytochrome C ◽  
Anticancer Agents ◽  
Mitochondrial Permeability Transition ◽  
Melanoma Cells ◽  
Biologically Active ◽  
Rat Liver Mitochondria ◽  
Caspase 8 ◽  
Human Leukemia ◽  
Cytochrome C Release ◽  
Merocyanine 540

If the interplay between caspase proteases and mitochondria decide the fate of the cell during apoptosis, they may constitute useful molecular targets for novel drug design. We have shown that photoactivated merocyanine 540 (pMC540) triggers caspase-mediated apoptosis in HL60 leukemia and M14 melanoma cells. Because pMC540 is a mixture of photoproducts, we set out to purify the biologically active component(s) from this mixture and to investigate their ability to directly activate intracellular caspases and/or trigger mitochondrial events associated with apoptosis. Two photoproducts, namely C1 and C2, purified and characterized by mass spectroscopy and nuclear magnetic resonance (NMR) analysis, effectively induced apoptosis in HL60 and M14 cells. Interestingly, both C1 and C2 induced non–receptor-dependent activation of caspase 8, which was responsible for the downstream activation of caspase 3 and cell death. Both compounds induced the release of cytochrome C from mitochondria of tumor cells and from purified rat liver mitochondria; however, different mechanisms were operative in cytochrome C translocation in response to C1 or C2. C1-induced cytochrome C release was mediated by the mitochondrial permeability transition (MPT) pore and accompanied by a decrease in mitochondrial transmembrane potential (▵ψm), whereas cytochrome C release in response to C2 was independent of MPT pore opening. These findings do not exclude the possibility that changes in mitochondrial ▵ψm are critical for apoptosis in some instances, but support the notion that this may not be a universal step in the apoptotic process. Thus, identification of two novel anticancer agents that directly activate effector components of the apoptotic pathway could have potential implications for the development of newer chemotherapeutic drugs.

scholarly journals Co-treatment of Garlic-Oils Extract, Dially-thiosulphate, and Histone Deacetylases Inhibitors (HDACI) Synergistically Inhibited Cell Proliferation and induced Apoptosis in Hepatocellular carcinoma cell lines

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S137-S137
Author(s):  
A S Fyala ◽  
A S Sultan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Cell Lines ◽  
Histone Deacetylases ◽  
Apoptosis Induction ◽  
Histone Deacetylases Inhibitors ◽  
Cycle Arrest ◽  
Induced Apoptosis

Abstract Introduction/Objective Hepatocellular carcinoma (HCC) is the most common cause of cancer-deaths worldwide. Garlic (Allium Sativum), is a natural-medicinal herb which has anti-fungal, anti-bacterial, anti-inflammatory, anti-virus, and antiproliferative activities. Garlic-oil soluble-sulfur-compounds, diallyl-thiosulphate, (DT) are more effective than water-soluble-compounds in protection against cancer due to its capacity to induce apoptosis and revise anti- multidrug-resistance. Histone deacetylases inhibitors (HDACIs) are inhibitors of anti-cancer agents that play a role in inducing death, differentiation, apoptosis induction, and cell-cycle arrest in different cancer-types. The present studying aims to investigate the anti-proliferative effect of organosulfur-oil DT extract of garlic by possible modulation of HDACIs role on HCC cell-lines. Methods/Case Report Two HDACIs, suberanilohydroxamic acid (SAHA) and trichostatinA (TSA), were used to investigate their role on proliferation of two HCC cell-lines, HepG2 and Hep3B, respectively. Cell proliferation was examined by Wst-1 assay, apoptosis induction signaling pathways, cell-cycle analysis, and western-blot analysis of the major oncogenic signaling pathways in the two tested cell-lines. Results (if a Case Study enter NA) Our data showed that DT significantly inhibited the cell-proliferation and induced cell-cycle arrest at G2/M phase in both HCC cell-lines. In addition, co-treatment of DT and HDACIs for 48h enhanced the cell inhibitory effect and induced apoptosis by up-regulation of p53, p21, and Bax protein expression and down- regulation of Bcl-2 and cyclin-D1 protein expression compared to control or each treatment alone. Furthermore, the data showed that DT significantly increased caspases-3 activity in Hep-G2 cell-line than that of Hep3B cell-line in a dose dependent-time compared to the control. Apoptosis induction was consistent with up-regulated caspase-3 activity, and HepG2 cells, but not Hep3B cells, showed a significant increase in response to co-treatment of DT with SAHA compared to co-treatment with TSA. Conclusion The data of the present study demonstrated that DT, non-toxicity compound, might be a new modulator for HDACIs effects, which in turn might be a promising prospective agent for HCC treatment.

Privileged Structures in the Design of Potential Drug Candidates for Neglected Diseases

2019 ◽  
Vol 26 (23) ◽  
pp. 4323-4354 ◽  
Author(s):  
Ana Cristina Lima Leite ◽  
José Wanderlan Pontes Espíndola ◽  
Marcos Veríssimo de Oliveira Cardoso ◽  
Gevanio Bezerra de Oliveira Filho
Keyword(s):  
Biologically Active ◽  
Neglected Diseases ◽  
Financial Return ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Wide Range ◽  
Methods Of Synthesis ◽  
Current Therapies ◽  
Resistant Strains ◽  
Privileged Structures

Background: Privileged motifs are recurring in a wide range of biologically active compounds that reach different pharmaceutical targets and pathways and could represent a suitable start point to access potential candidates in the neglected diseases field. The current therapies to treat these diseases are based in drugs that lack of the desired effectiveness, affordable methods of synthesis and allow a way to emergence of resistant strains. Due the lack of financial return, only few pharmaceutical companies have been investing in research for new therapeutics for neglected diseases (ND). Methods: Based on the literature search from 2002 to 2016, we discuss how six privileged motifs, focusing phthalimide, isatin, indole, thiosemicarbazone, thiazole, and thiazolidinone are particularly recurrent in compounds active against some of neglected diseases. Results: It was observed that attention was paid particularly for Chagas disease, malaria, tuberculosis, schistosomiasis, leishmaniasis, dengue, African sleeping sickness (Human African Trypanosomiasis - HAT) and toxoplasmosis. It was possible to verify that, among the ND, antitrypanosomal and antiplasmodial activities were between the most searched. Besides, thiosemicarbazone moiety seems to be the most versatile and frequently explored scaffold. As well, phthalimide, isatin, thiazole, and thiazolidone nucleus have been also explored in the ND field. Conclusion: Some described compounds, appear to be promising drug candidates, while others could represent a valuable inspiration in the research for new lead compounds.

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