Aspirin antagonizes the cytotoxic effect of methotrexate in lung cancer cells

Kun Huang Yan, Liang Ming Lee, Mao-Chih Hsieh, Ming De Yan, Chih Jung Yao, Pey Yi Chang, Tsung Li Chen, Hwan You Chang, Ann Lii Cheng, Gi Ming Lai, Shuang En Chuang

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Methotrexate (MTX) has been widely used for the treatment of cancer and rheumatoid arthritis (RA). Aspirin (ASA) is a non-selective cyclooxygenase (COX) inhibitor that contributes to the treatment of inflammatory conditions such as RA. It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression, induction of apoptosis and inhibition of angiogenesis. In the present study, we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by SRB and colony formation assays. ASA alleviated the MTX-mediated S phase accumulation and recovered the G1 phase. MTX-mediated accumulation of the S phase marker cyclin A was also alleviated by ASA. Notably, FAS protein levels were upregulated by MTX in A549 cells. The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase-3, Bcl-2 and FAS but not dihydrofolate reductase (DHFR). This suggests that the alteration of caspase-3, Bcl-2 and FAS was involved in the antagonism between ASA and MTX. Exogenously added folic acid reversed the MTX-mediated DHFR inhibition following either MTX or MTX + ASA treatments. Most importantly, we demonstrated for the first time that the commonly used non-steroidal anti-inflammatory drug for headache ASA and possibly other COX-1/2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX. The clinical implication of our finding is obvious, i.e., the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should.

Original languageEnglish
Pages (from-to)1497-1505
Number of pages9
JournalOncology Reports
Volume30
Issue number3
DOIs
Publication statusPublished - Sep 2013

Fingerprint

Methotrexate
Aspirin
Lung Neoplasms
Tetrahydrofolate Dehydrogenase
S Phase
Caspase 3
Rheumatoid Arthritis
Therapeutics
Cyclin A
Cyclooxygenase 1
Cyclooxygenase Inhibitors
Cyclooxygenase 2 Inhibitors
G1 Phase
Folic Acid
Headache
Cell Cycle
Anti-Inflammatory Agents
Apoptosis

Keywords

  • Antagonism
  • Aspirin
  • Methotrexate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Aspirin antagonizes the cytotoxic effect of methotrexate in lung cancer cells. / Yan, Kun Huang; Lee, Liang Ming; Hsieh, Mao-Chih; Yan, Ming De; Yao, Chih Jung; Chang, Pey Yi; Chen, Tsung Li; Chang, Hwan You; Cheng, Ann Lii; Lai, Gi Ming; Chuang, Shuang En.

In: Oncology Reports, Vol. 30, No. 3, 09.2013, p. 1497-1505.

Research output: Contribution to journalArticle

Yan, KH, Lee, LM, Hsieh, M-C, Yan, MD, Yao, CJ, Chang, PY, Chen, TL, Chang, HY, Cheng, AL, Lai, GM & Chuang, SE 2013, 'Aspirin antagonizes the cytotoxic effect of methotrexate in lung cancer cells', Oncology Reports, vol. 30, no. 3, pp. 1497-1505. https://doi.org/10.3892/or.2013.2561
Yan, Kun Huang ; Lee, Liang Ming ; Hsieh, Mao-Chih ; Yan, Ming De ; Yao, Chih Jung ; Chang, Pey Yi ; Chen, Tsung Li ; Chang, Hwan You ; Cheng, Ann Lii ; Lai, Gi Ming ; Chuang, Shuang En. / Aspirin antagonizes the cytotoxic effect of methotrexate in lung cancer cells. In: Oncology Reports. 2013 ; Vol. 30, No. 3. pp. 1497-1505.
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AU - Lee, Liang Ming

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AU - Yan, Ming De

AU - Yao, Chih Jung

AU - Chang, Pey Yi

AU - Chen, Tsung Li

AU - Chang, Hwan You

AU - Cheng, Ann Lii

AU - Lai, Gi Ming

AU - Chuang, Shuang En

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AB - Methotrexate (MTX) has been widely used for the treatment of cancer and rheumatoid arthritis (RA). Aspirin (ASA) is a non-selective cyclooxygenase (COX) inhibitor that contributes to the treatment of inflammatory conditions such as RA. It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression, induction of apoptosis and inhibition of angiogenesis. In the present study, we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by SRB and colony formation assays. ASA alleviated the MTX-mediated S phase accumulation and recovered the G1 phase. MTX-mediated accumulation of the S phase marker cyclin A was also alleviated by ASA. Notably, FAS protein levels were upregulated by MTX in A549 cells. The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase-3, Bcl-2 and FAS but not dihydrofolate reductase (DHFR). This suggests that the alteration of caspase-3, Bcl-2 and FAS was involved in the antagonism between ASA and MTX. Exogenously added folic acid reversed the MTX-mediated DHFR inhibition following either MTX or MTX + ASA treatments. Most importantly, we demonstrated for the first time that the commonly used non-steroidal anti-inflammatory drug for headache ASA and possibly other COX-1/2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX. The clinical implication of our finding is obvious, i.e., the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should.

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