Cytotoxicity of Hydrazones of Morpholine Bearing Mannich Bases Towards Huh7 and T47D Cell Lines and Their Effects on Mitochondrial Respiration

Background: Chemotherapy is one of the mainstays of cancer treatment, despite the serious side effects of the clinically available anticancer drugs. In recent years increasing attention has been directed towards novel agents with improved efficacy and selectivity. Compounds with chalcone backbone have been reported to possess various biological activities such as anticancer, antimicrobial, anti-inflammatory, analgesic, antioxidant, etc. It was reported that aminomethylation of hydroxy chalcones to the corresponding Mannich bases increased their cytotoxicity. In this context, our interest has been focused on the design and synthesis of the so-called multi-target molecules, containing two or more pharmacophore fragments. Methods: A series of Mannich bases were synthesized by the reaction between 6-[3-(3,4,5- trimethoxyphenyl)-2-propenoyl]-2(3Н)-benzoxazolone, formaldehyde, and a secondary amine. The structures of the compounds were confirmed by elemental analysis, IR and NMR spectra. The new Mannich bases were evaluated for their in vitro cytotoxicity against a panel of human tumor cell lines, including BV-173, SKW-3, K-562, HL-60, HD-MY-Z and MDA-MB-231. The effects of selected compounds on the cellular levels of glutathione (GSH) were determined. Results: The new compounds 4a-e exhibited concentration-dependent cytotoxic effects at micromolar concentrations in MTT-dye reduction assay against a panel of human tumor cell lines, similar to those of starting chalcone 3. The tested agents led to concentration - dependent depletion of cellular GSH levels, whereby the effects of the chalcone prototype 3 and its Mannich base-derivatives were comparable. Conclusion: The highest chemosensitivity to the tested compounds was observed in BV- 173followed by SKW-3 and HL-60 cell lines.

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CYTOTOXIC ACTIVITY OF AVOCADO SEEDS EXTRACTS (PERSEA AMERICANA MILL.) ON T47D CELL LINES

International Research Journal of Pharmacy ◽

10.7897/2230-8407.0507113 ◽

2014 ◽

Vol 5 (7) ◽

pp. 557-559 ◽

Cited By ~ 7

Author(s):

Elenora Kristanty Ruth ◽

Suriawati Junie ◽

Sulistiyo Joko

Keyword(s):

Cytotoxic Activity ◽

Cell Lines ◽

T47d Cell ◽

Persea Americana

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Cytotoxic and Apoptotic-inducing Effect of Fraction Containing Brazilein from Caesalpinia sappan L. and Cisplatin on T47D Cell Lines

Indonesian Journal of Cancer Chemoprevention ◽

10.14499/indonesianjcanchemoprev6iss3pp89-96 ◽

2017 ◽

Vol 6 (3) ◽

pp. 89

Author(s):

Prisnu Tirtanirmala ◽

Annisa Novarina ◽

Rohmad Yudi Utomo ◽

Raisatun Nisa Sugiyanto ◽

Riris Istighfari Jenie ◽

...

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Annexin V ◽

T47d Cell ◽

Breast Cancer Cell Lines ◽

Cytotoxic Effects ◽

Caesalpinia Sappan ◽

Main Compound ◽

T47d Breast Cancer Cell ◽

Ic50 Value

Anticancer activity of secang’s heartwood (Caesalpinia sappan L.) is based on its main compound: brazilin and brazilein. Brazilin, brazilein, and other compounds such as caesalpiniaphenol can affect proteins that have a role in apoptosis. In this study, we observed cytotoxic activity of fraction containing brazilein (FCB) alone or in combination with chemotherapeutic agent, cisplatin and the ability of the combination to induce apoptosis in T47D breast cancer cell lines. Cytotoxicity assay was determined using MTT assay, whereas the detection apoptosis induction was conducted using flow cytometry using Annexin-V and propidium iodide. FCB and cisplatin showed cytotoxic effect on T47D cells with IC50 value of 68 µg/mL and 16 µM, respectively. Combination of FCB and cisplatin result synergistic combination at the concentration ratio of 1/2 IC50 with CI value of 0.66. Its combination also able to induce apoptosis on T47D cell population 13% larger than the single treatment. Based on this study, we conclude that FCB is able to enhance the cytotoxic effects of cisplatin by inducing apoptosis.Keywords: Caesalpinia sappan L., cisplatin, apoptosis, breast cancer

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Synthesis of Novel 2(3H)-Benzoxazolone Mannich Bases as Potential Agents for Future Studies of Cancer Treatment

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2020/v32i4431077 ◽

2021 ◽

pp. 23-30

Author(s):

Emine Erdag

Keyword(s):

Cytotoxic Activity ◽

Cell Lines ◽

Cancer Cell ◽

In Silico ◽

Cancer Cell Lines ◽

Mannich Bases ◽

Pharmaceutical Chemistry ◽

Cytotoxic Activities ◽

In Silico Prediction ◽

Cytotoxicity Studies

Aims: In this study, a series of new Mannich bases of 2(3H)-benzoxazolone derivatives containing substituted cyclic amine moieties with a potential to show cytotoxic activity have been prepared. In order to develop effective anticancer agents against various cancer cell lines, it is essential to study the structure activity relationship and the effect of different substituents on the activity of heterocyclic scaffolds which were known to have cytotoxic activities. Study Design: In silico and experimental design. Place and Duration of Study: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Near East University, Nicosia, Cyprus, between January 2019- September 2020. Methodology: In this work, 2(3H)-benzoxazolone derivatives were prepared by Mannich reaction. The synthesis and structural characterization of the compounds were performed experimentally by FT-IR, 1H NMR, 13C NMR spectra and elemental analysis. In silico prediction of cell line cytotoxicity with PASS based CLC-Pred tool was performed to predict cytotoxicity of the compounds against different tumor cell lines. Results: In silico prediction results for the compounds showed that all benzoxazolone derivatives have cytotoxic activity against different cell lines and tumor types. It was clearly understood that the cytotoxicity of the compounds was affected by the substituents on their piperazine moieties and by the substituents on benzoxazolone core structure. Conclusion: In conclusion, newly synthesized Mannich bases of benzoxazolone derivatives were reported for the first time which may have a potential to show anticancer activities at different cancer cell lines. The efficiency of new compounds against cancer could be found via PASS based CLC-Pred database and could be further investigated by in vivo experimental cytotoxicity studies in the future to design new anticancer drug candidates.

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Antioxidant Properties and Cytotoxic Activity of Ethyl Acetate Fraction of Plectranthus amboinicus (Lour.) Spreng. Leaves on HeLa and T47D Cell Lines

Indonesian Journal of Cancer Chemoprevention ◽

10.14499/indonesianjcanchemoprev10iss1pp37-45 ◽

2019 ◽

Vol 10 (1) ◽

pp. 37

Author(s):

Poppy Anjelisa Zaitun Hasibuan ◽

Panal Sitorus ◽

Denny Satria ◽

Rizka Damela Sibuea

Keyword(s):

Ethyl Acetate ◽

Cytotoxic Activity ◽

Cell Lines ◽

Mcf7 Cell ◽

Ethyl Acetate Extract ◽

Antioxidant Properties ◽

T47d Cell ◽

Flavonoid Content ◽

Dpph Method ◽

Plectranthus Amboinicus

Research into plants with anticancer effects is actively encouraged in orderto discover new drugs with lessertoxicity but more potent effects. The aims of study are to evaluate the antioxidant properties and to investigate the cytotoxic activity of Plectranthus amboinicus (Lour.) Spreng. leaves ethyl acetate fractions on HeLa,T47D and MCF7 cell lines. The extract was prepared by graded maceration using n-hexane and ethyl acetate. The ethyl acetate extract was fractionated in vacuum liquid chromatography with n-hexane: ethyl acetate; and ethyl acetate: methanol as mobile phase. Then, the fractions were analyzed with thin layer chromatography (TLC). The free radical scavenging activity was measured by DPPH method, the total flavonoid content was calculated by quercetin equivalent and the absorbance is measured by using UV-Visible spectrophotometry. The cytotoxic activity were determined using MTT assay. The fractions contained 5 sub fractions with same TLC profile. The fractions showed antioxidant activity by DPPH method with different IC50 values, namely: 130 µg/mL(I), 127 µg/mL(II), 137 µg/mL(III), 129 µg/mL(IV), and 124 µg/ mL(V), respectively. The measurement of total flavonoid content showed 118 mg QE/g (I), 50 mg QE/g (II), 207 mg QE/g (III), 56 mg QE/g (IV), and 55 mg QE/g (V). The IC50 of each sub fractions on HeLa cell were 77 µg/mL, 46 µg/mL, 93 µg/mL, 71 µg/mL and 476 µg/mL; for T47D cell were 1621 µg/mL, 111 µg/mL, 128 µg/mL, 150 µg/mL and 209 µg/mL; and for MCF7 were 259 µg/mL, 343 µg/mL, 575 µg/mL, 408 µg/mL and 250 µg/mL. Based on the results, the fractions derived from ethyl acetate extract of Plectranthus amboinicus (Lour.) Spreng. leaves exhibit antioxidant. The Fraction II from ethyl acetate extract of Plectranthus amboinicus (Lour.) Spreng. was the most cytotoxic on HeLa, T47D and MCF7 cell lines. It is potential to undergo further isolation of its cytotoxic compounds.Keywords : antioxidant, cytotoxic, Plectranthus amboinicul (Lour.) Spreng., ethyl acetate fractions

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Cytochrome C Oxidase Subunit 4 (COX4): A Potential Therapeutic Target for the Treatment of Medullary Thyroid Cancer

Cancers ◽

10.3390/cancers12092548 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2548

Author(s):

Athanasios Bikas ◽

Kirk Jensen ◽

Aneeta Patel ◽

John Costello ◽

Sarah Reynolds ◽

...

Keyword(s):

Thyroid Cancer ◽

Cytochrome C ◽

Cytochrome C Oxidase ◽

Cell Lines ◽

Cancer Progression ◽

Mitochondrial Respiration ◽

Thyroid Tissue ◽

Human Thyroid ◽

Atp Production ◽

Tt Cells

The nuclear-encoded subunit 4 of cytochrome c oxidase (COX4) plays a role in regulation of oxidative phosphorylation and contributes to cancer progression. We sought to determine the role of COX4 in differentiated (DTC) and medullary (MTC) thyroid cancers. We examined the expression of COX4 in human thyroid tumors by immunostaining and used shRNA-mediated knockdown of COX4 to evaluate its functional contributions in thyroid cancer cell lines. In human thyroid tissue, the expression of COX4 was higher in cancers than in either normal thyroid (p = 0.0001) or adenomas (p = 0.001). The level of COX4 expression correlated with tumor size (p = 0.04) and lymph-node metastases (p = 0.024) in patients with MTCs. COX4 silencing had no effects on cell signaling activation and mitochondrial respiration in DTC cell lines (FTC133 and BCPAP). In MTC-derived TT cells, COX4 silencing inhibited p70S6K/pS6 and p-ERK signaling, and was associated with decreased oxygen consumption and ATP production. Treatment with potassium cyanide had minimal effects on FTC133 and BCPAP, but inhibited mitochondrial respiration and induced apoptosis in MTC-derived TT cells. Our data demonstrated that metastatic MTCs are characterized by increased expression of COX4, and MTC-derived TT cells are vulnerable to COX4 silencing. These data suggest that COX4 can be considered as a novel molecular target for the treatment of MTC.

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Key parameter optimization using multivariable linear model for the evaluation of the in vitro estrogenic activity assay in T47D cell lines (CXCL‐test)

Journal of Applied Toxicology ◽

10.1002/jat.4280 ◽

2021 ◽

Author(s):

Lucie Linhartova ◽

Nathalie Costet ◽

Farzad Pakdel ◽

Tomas Cajthaml ◽

Denis Habauzit

Keyword(s):

Linear Model ◽

Cell Lines ◽

Parameter Optimization ◽

Estrogenic Activity ◽

T47d Cell ◽

Activity Assay ◽

Key Parameter

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Mannich Bases: Centrality in Cytotoxic Drug Design

Medicinal Chemistry ◽

10.2174/1573406418666211220124119 ◽

2021 ◽

Vol 18 ◽

Author(s):

Neha V. Bhilare ◽

Vinayak S. Marulkar ◽

Pramodkumar J. Shirote ◽

Shailaja A. Dombe ◽

Vilas J. Pise ◽

...

Keyword(s):

Drug Design ◽

Drug Development ◽

Cell Lines ◽

Mannich Bases ◽

Cytotoxic Agents ◽

Structure Activity ◽

Anti Cancer ◽

Methods Of Synthesis ◽

Future Drug ◽

Clinical Conditions

: Mannich bases identified by Professor Carl Mannich have been the most extensively explored scaffolds for more than 100 years now. The versatile biological roles that they play have promoted their applications in many clinical conditions. The present review highlights the application of Mannich bases as cytotoxic agents, categorizing them into synthetic, semisynthetic and prodrugs classes and gives an exhaustive account of the work reported in the last two decades. The methods of synthesis of these cytotoxic agents, their anti-cancer potential in various cell lines and promising leads for future drug development have also been discussed. Structure-activity relationships along with the targets on which these cytotoxic Mannich bases act have been included as well.

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APOPTOSIS INDUCTION EFFECT OF CURCUMIN AND ITS ANALOGS PENTAGAMAVUNON-0 AND PENTAGAMAVUNON-1 ON CANCER CELL LINES

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i3.16311 ◽

2017 ◽

Vol 10 (3) ◽

pp. 373 ◽

Cited By ~ 2

Author(s):

Muhammad Da'i ◽

Andi Suhendi ◽

Edi Meiyanto ◽

Umar Anggoro Jenie ◽

Masashi Kawaichi

Keyword(s):

Cell Growth ◽

Western Blot ◽

Cell Lines ◽

Cancer Cell ◽

Morphological Changes ◽

Cancer Cell Line ◽

T47d Cell ◽

Cancer Cell Lines ◽

Induction Effect ◽

Apoptosis Induction

ABSTRACTObjectives: This experiment aims to investigate the apoptosis effect of curcumin and its analogs pentagamavunon-0 (PGV-0) and PGV-1 on normaland other cancer cell lines.Methods: Growth inhibition effect was investigated using the MTT method. Double staining used acridine orange, 2-(4-aminodiphenyl)-6-indolcarbamidine dihydrochloride and ethidium bromide was performed to determine morphological changes of cells. Detection of PARP, caspase-3,PUMA and BAX using a western blot method was conducted to elucidate the apoptosis effect of the compounds.Results: PGV-1 (2.5 μM) and PGV-0 (5.0 μM) could inhibit T47D-cell growth on 72 h observation, but not for curcumin. DNA staining showed PGV-1has the strongest apoptosis induction effect on T47D-cells compared to PGV-0 and curcumin as well. Western blot analysis resulted in cleavage PARP(83 kD) on HeLa, T47D, and MCF-7 cells treated with PGV-1 (2.5 μM), PGV-0 (5.0 μM). Curcumin (10.0 μM) just induced apoptosis on T47D-cell andMCF-7 cell, but not HeLa cell. Cleavage PARP resulted by apoptosis process in the cell. PGV-1 (2.5 μM) had a stronger apoptosis effect compared toPGV-0 (5.0 μM) and curcumin (10.0 μM) based on cleaved PARP result qualitatively. On the normal cell (NH3T3), cells that were treated with thecompounds resulted in a negative cleavage PARP. This result indicated that the compounds were part of a selectively induced cancer cell line apoptosisprocess.Conclusion: Curcumin, PGV-0 and PGV-1 could inhibit cell growth by induce apoptosis on cancer cells but not on normal cells, which PGV-1 hasstrongest apoptosis induction effect on cancer cell lines.Keywords: Curcumin and analogs, Apoptosis, Cancer cell lines.

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Heterogeneity of Metabolic Vulnerability in Imatinib-Resistant Gastrointestinal Stromal Tumor

Cells ◽

10.3390/cells9061333 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1333

Author(s):

Wen-Kuan Huang ◽

Jiwei Gao ◽

Ziqing Chen ◽

Hao Shi ◽

Juan Yuan ◽

...

Keyword(s):

Cell Lines ◽

Mitochondrial Respiration ◽

Resistant Cell ◽

Resistant Cell Line ◽

Metabolic Reprogramming ◽

Peroxisome Proliferator ◽

Imatinib Treatment ◽

Peroxisome Proliferator Activated Receptor ◽

Glycolytic Activity ◽

Imatinib Resistant

Metabolic reprogramming is a hallmark of cancer cells in response to targeted therapy. Decreased glycolytic activity with enhanced mitochondrial respiration secondary to imatinib has been shown in imatinib-sensitive gastrointestional stromal tumors (GIST). However, the role of energy metabolism in imatinib-resistant GIST remains poorly characterized. Here, we investigated the effect of imatinib treatment on glycolysis and oxidative phosphorylation (OXPHOS), as well as the effect of inhibition of these energy metabolisms on cell viability in imatinib-resistant and -sensitive GIST cell lines. We observed that imatinib treatment increased OXPHOS in imatinib-sensitive, but not imatinib-resistant, GIST cells. Imatinib also reduced the expression of mitochondrial biogenesis activators (peroxisome proliferator-activated receptor coactivator-1 alpha (PGC1α), nuclear respiratory factor 2 (NRF2), and mitochondrial transcription factor A (TFAM)) and mitochondrial mass in imatinib-sensitive GIST cells. Lower TFAM levels were also observed in imatinib-sensitive GISTs than in tumors from untreated patients. Using the Seahorse system, we observed bioenergetics diversity among the GIST cell lines. One of the acquired resistant cell lines (GIST 882R) displayed a highly metabolically active phenotype with higher glycolysis and OXPHOS levels compared with the parental GIST 882, while the other resistant cell line (GIST T1R) had a similar basal glycolytic activity but lower mitochondrial respiration than the parental GIST T1. Further functional assays demonstrated that GIST 882R was more vulnerable to glycolysis inhibition than GIST 882, while GIST T1R was more resistant to OXPHOS inhibition than GIST T1. These findings highlight the diverse energy metabolic adaptations in GIST cells that allow them to survive upon imatinib treatment and reveal the potential of targeting the metabolism for GIST therapy.

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