Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs’ Cytotoxicity, Metabolism and Cellular Response

Activity modulation of drug metabolism enzymes can change the biotransformation of chemotherapeutics and cellular responses induced by them. As a result, drug-drug interactions can be modified. Acridinone derivatives, represented here by C-1305 and C-1311, are potent anticancer drugs. Previous studies in non-cellular systems showed that they are mechanism-based inhibitors of cytochrome P4503A4 and undergo glucuronidation via UDP-glucuronosyltranspherase 1A10 isoenzyme (UGT1A10). Therefore, we investigated the potency of these compounds to modulate P4503A4 and UGT1A10 activity in breast MCF-7 and colon HCT116 cancer cells and their influence on cytotoxicity and cellular response in cells with different expression levels of studied isoenzymes. We show that C-1305 and C-1311 are inducers of not only P4503A4 but also UGT1A10 activity. MCF-7 and HCT116 cells with high P4503A4 activity are more sensitive to acridinone derivatives and undergo apoptosis/necrosis to a greater extent. UGT1A10 was demonstrated to be responsible for C-1305 and C-1311 glucuronidation in cancer cells and glucuronide products were excreted outside the cell very fast. Finally, we show that glucuronidation of C-1305 antitumor agent enhances its pro-apoptotic properties in HCT116 cells, while the cytotoxicity and cellular response induced by C-1311 did not change after drug glucuronidation in both cell lines.

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Cytotoxic Effect of the Combination of Gemcitabine and Atorvastatin Loaded in Microemulsion on the HCT116 Colon Cancer Cells

International Journal of Pharmaceutical and Clinical Research ◽

10.25258/ijpcr.v9i2.8298 ◽

2017 ◽

Vol 9 (2) ◽

Cited By ~ 1

Author(s):

Mayson H. Alkhatib ◽

Dalal Al-Saedi ◽

Wadiah S. Backer

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Anticancer Drugs ◽

Therapeutic Potential ◽

Morphological Changes ◽

In Vitro Study ◽

Colon Cancer Cells ◽

Apoptosis Detection ◽

Hct116 Cells

The combination of anticancer drugs in nanoparticles has great potential as a promising strategy to maximize efficacies by eradicating resistant, reduce the dosage of the drug and minimize toxicities on the normal cells. Gemcitabine (GEM), a nucleoside analogue, and atorvastatin (ATV), a cholesterol lowering agent, have shown anticancer effect with some limitations. The objective of this in vitro study was to evaluate the antitumor activity of the combination therapy of GEM and ATVencapsulated in a microemulsion (ME) formulation in the HCT116 colon cancer cells. The cytotoxicity and efficacy of the formulation were assessed by the 3- (4,5dimethylthiazole-2-yl)-2,5-diphyneltetrazolium bromide (MTT) assay. The mechanism of cell death was examined by observing the morphological changes of treated cells under light microscope, identifying apoptosis by using the ApopNexin apoptosis detection kit, and viewing the morphological changes in the chromatin structure stained with 4′,6-diamidino-2-phenylindole (DAPI) under the inverted fluorescence microscope. It has been found that reducing the concentration of GEM loaded on ME (GEM-ME) from 5μM to 1.67μM by combining it with 3.33μM of ATV in a ME formulation (GEM/2ATV-ME) has preserved the strong cytotoxicity of GEM-ME against HCT116 cells. The current study proved that formulating GEM with ATV in ME has improved the therapeutic potential of GEM and ATV as anticancer drugs.

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Circadian Timekeeping in Anticancer Therapeutics: An Emerging Vista of Chronopharmacology Research

Current Drug Metabolism ◽

10.2174/1389200222666211119103422 ◽

2021 ◽

Vol 22 ◽

Author(s):

Alekhya Puppala ◽

Sourbh Rankawat ◽

Sandipan Ray

Keyword(s):

Drug Metabolism ◽

Circadian Clock ◽

Cancer Cells ◽

Anticancer Drugs ◽

Cancer Biology ◽

Anticancer Therapy ◽

Time Of Day ◽

Circadian Regulation ◽

Cancer Management ◽

Anticancer Therapeutics

Background: Intrinsic rhythms in host and cancer cells play an imperative role in tumorigenesis and anticancer therapy. Circadian medicine in cancer is principally reliant on the control of growth and development of cancer cells or tissues by targeting the molecular clock and implementing time-of-day-based anticancer treatments for therapeutic improvements. In recent years, based on extensive high-throughput studies, we witnessed the arrival of several drugs and drug-like compounds that can modulate circadian timekeeping for therapeutic gain in cancer management. Objective: This perspective article intends to illustrate the current trends in circadian medicine in cancer, focusing on clock-modulating pharmacological compounds and circadian regulation of anticancer drug metabolism and efficacy. Scope and Approach: Considering the critical roles of the circadian clock in metabolism, cell signaling, and apoptosis, chronopharmacology research is exceedingly enlightening for understanding cancer biology and improving anticancer therapeutics. In addition to reviewing the relevant literature, we investigated the rhythmic expression of molecular targets for many anticancer drugs frequently used to treat different cancer types. Key Findings and Conclusion: There are adequate empirical pieces of evidence supporting circadian regulation of drug metabolism, transport, and detoxification. Administration of anticancer drugs at specific dosing times can improve their effectiveness and reduce the toxic effects. Moreover, pharmacological modulators of the circadian clock could be used for targeted anticancer therapeutics such as boosting circadian rhythms in the host can markedly reduce the growth and viability of tumors. All in all, precision chronomedicine can offer multiple advantages over conventional anticancer therapy.

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Effect of Distinct Anticancer Drugs on the Phosphorylation of p53 Protein at Serine 46 in Human MCF-7 Breast Cancer Cells

Annals of the New York Academy of Sciences ◽

10.1196/annals.1397.006 ◽

2007 ◽

Vol 1095 (1) ◽

pp. 45-52 ◽

Cited By ~ 4

Author(s):

J. WESIERSKA-GADEK ◽

M. GUEORGUIEVA ◽

I. HERBACEK ◽

C. RANFTLER

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Anticancer Drugs ◽

Breast Cancer Cells ◽

P53 Protein ◽

Mcf 7

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Abstract LT014: Extracellular matrix stiffness regulates cellular response to anticancer drugs in breast and lung cancer cells

10.1158/1538-7445.tme21-lt014 ◽

2021 ◽

Author(s):

Atul Bharde ◽

Snigdha Nadagauda ◽

Megha Gaur ◽

Vaishnavi Borade

Keyword(s):

Lung Cancer ◽

Extracellular Matrix ◽

Cancer Cells ◽

Anticancer Drugs ◽

Cellular Response ◽

Lung Cancer Cells ◽

Matrix Stiffness ◽

Extracellular Matrix Stiffness

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65 Phase II drug metabolism UGT1A enzyme affects cellular response of colon cancer cells to antitumor triazoloacridinone C-1305 treatment

European Journal of Cancer ◽

10.1016/s0959-8049(14)70191-1 ◽

2014 ◽

Vol 50 ◽

pp. 26

Author(s):

E. Augustin ◽

E. Bartusik ◽

A. Theus ◽

B. Borowa-Mazgaj ◽

Z. Mazerska

Keyword(s):

Colon Cancer ◽

Drug Metabolism ◽

Cancer Cells ◽

Phase Ii ◽

Cellular Response ◽

Colon Cancer Cells ◽

Phase Ii Drug Metabolism

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Assessment of Cellular Responses to Oxidative Stress using MCF-7 Breast Cancer Cells, Black Seed (N. Sativa L.) Extracts and H2O2

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph2005030005 ◽

2005 ◽

Vol 2 (3) ◽

pp. 411-419 ◽

Cited By ~ 12

Author(s):

Ibrahim Farah

Keyword(s):

Breast Cancer ◽

Oxidative Stress ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cellular Responses ◽

Black Seed ◽

Mcf 7

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Inhibition of c-Jun N-Terminal Kinase 2 Expression Suppresses Growth and Induces Apoptosis of Human Tumor Cells in a p53-Dependent Manner

Molecular and Cellular Biology ◽

10.1128/mcb.20.5.1713-1722.2000 ◽

2000 ◽

Vol 20 (5) ◽

pp. 1713-1722 ◽

Cited By ~ 95

Author(s):

Olga Potapova ◽

Myriam Gorospe ◽

Ryan H. Dougherty ◽

Nicholas M. Dean ◽

William A. Gaarde ◽

...

Keyword(s):

Cellular Response ◽

Kinase Inhibitor ◽

Critical Role ◽

Human Tumor ◽

Dependent Manner ◽

Cyclin Dependent Kinase Inhibitor ◽

Downstream Effector ◽

Regulatory Functions ◽

Hct116 Cells ◽

Mcf 7

ABSTRACT c-Jun N-terminal kinase (JNK) plays a critical role in coordinating the cellular response to stress and has been implicated in regulating cell growth and transformation. To investigate the growth-regulatory functions of JNK1 and JNK2, we used specific antisense oligonucleotides (AS) to inhibit their expression. A survey of several human tumor cell lines revealed that JNKAS treatment markedly inhibited the growth of cells with mutant p53 status but not that of cells with normal p53 function. To further examine the influence of p53 on cell sensitivity to JNKAS treatment, we compared the responsiveness of RKO, MCF-7, and HCT116 cells with normal p53 function to that of RKO E6, MCF-7 E6, and HCT116 p53−/−, which were rendered p53 deficient by different methods. Inhibition of JNK2 (and to a lesser extent JNK1) expression dramatically reduced the growth of p53-deficient cells but not that of their normal counterparts. JNK2AS-induced growth inhibition was correlated with significant apoptosis. JNK2AS treatment induced the expression of the cyclin-dependent kinase inhibitor p21 Cip1/Waf1 in parental MCF-7, RKO, and HCT116 cells but not in the p53-deficient derivatives. That p21 Cip1/Waf1 expression contributes to the survival of JNK2AS-treated cells was supported by additional experiments demonstrating that p21 Cip1/Waf1 deficiency in HCT116 cells also results in heightened sensitivity to JNKAS treatment. Our results indicate that perturbation of JNK2 expression adversely affects the growth of otherwise nonstressed cells. p53 and its downstream effector p21 Cip1/Waf1 are important in counteracting these detrimental effects and promoting cell survival.

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2-Methoxy-estradiol Loaded Alpha Lipoic Acid Nanoparticles Augment Cytotoxicity in MCF-7 Breast Cancer Cells

Dose-Response ◽

10.1177/15593258211055023 ◽

2021 ◽

Vol 19 (4) ◽

pp. 155932582110550

Author(s):

Nabil A. Alhakamy ◽

Mohammed W. Al-Rabia ◽

Hani Z. Asfour ◽

Samah Alshehri ◽

Waleed S. Alharbi ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Anticancer Drugs ◽

Lipoic Acid ◽

Breast Cancer Cells ◽

Entrapment Efficiency ◽

Fold Increase ◽

Alpha Lipoic Acid ◽

P53 Expression ◽

Mcf 7

The therapeutic effectiveness of anticancer drugs with a selective target for the nucleus of cancer cells may be improved by experimental approaches. In this regard, the formulation of anticancer drugs is considered one of the best ways to improve their effectiveness in targeting cancerous tissues. To enhance the anticancer activity of 2-methoxy-estradiol (2 ME) for breast cancer, 2-methoxyestradiol loaded alpha lipoic acid nanoparticles have been formulated. The prepared formula was observed to be spherical with a nanometer-scale and low PDI size (.234). The entrapment efficiency of the 2ME-ALA NPs was 87.32 ± 2.21% with > 85% release of 2 ME within 24 h. There was a 1.2-fold increase in apoptosis and a 3.46-fold increase in necrosis of the MCF-7 cells when incubated with 2ME-ALA NPs when compared to control cells. This increased apoptosis was also associated with increased ROS and increased p53 expression in 2ME-ALA NPs treated cells compared to the raw-2 ME group. Evaluation of cell-cycle data showed a substantial arrest of the G2-M phase of the MCF-7 cells when incubated with 2ME-ALA NPs. At the same time, a dramatically increased number of pre-G1 cells showed the increased apoptotic potential of the 2 ME when administered via the proposed formulation. In the end, the differential upregulation of caspase-3, p53, and ROS in MCF-7 cells established the superiority of the 2ME-ALA-Ms approach in targeting breast cancer. In summary, these results demonstrate that 2ME-ALA NPs are an efficient delivery tool for controlling the growth of breast cancer cells.

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