Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells

Journal Article · Thu Sep 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.06.019· OSTI ID:21587838

Saleh, Ekram M ^[1]; Ezz, Marwa ^[2]; Elsayed, Abeer M ^[3]

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1. Clinical Biochemistry and Molecular Biology unit, Department of Cancer Biology, National, Cancer Institute, Cairo University, Fom El-Khalig, Cairo (Egypt)
2. College of Pharmacy, Cairo University, Cairo (Egypt)
3. Tissue Culture unit, Pathology Department, National Cancer Institute, Cairo University (Egypt)

Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide {+-} celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. - Graphical abstract: Display Omitted Highlights: > Celecoxib may enhance effects of anticancer drugs. > Its combination with four drugs was tested in five cancer cell lines. > It antagonized the effects of the four drugs in the breast cancer cell line MCF7. > Doxorubicin's cytotoxic effects were antagonized by celecoxib in four cell lines. > Cell cycle, apoptosis and DNA damage explain the different interactive effects.

• OSTI ID: 21587838
• Journal Information: Toxicology and Applied Pharmacology, Vol. 255, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.06.019; PII: S0041-008X(11)00243-2; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CELL CYCLE
CHEMOTHERAPY
CLINICAL TRIALS
DNA
DNA DAMAGES
DOXORUBICIN
IN VIVO
INTERACTIONS
MAMMARY GLANDS
MITOSIS
NEOPLASMS
SENSITIVITY
ANTIBIOTICS
ANTI-INFECTIVE AGENTS
ANTINEOPLASTIC DRUGS
BODY
CELL DIVISION
DISEASES
DRUGS
GLANDS
MEDICINE
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANS
TESTING
THERAPY