Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines

Laura A. Martello, Hayley M. McDaid, Donna Lee Regl, Chia-Ping H. Yang, Dongfang Meng, Thomas R R Pettus, Michael D. Kaufman, Hirokazu Arimoto, Samuel J. Danishefsky, Amos B. Smith, Susan Band Horwitz

Research output: Contribution to journalArticle

170 Citations (Scopus)

Abstract

Recently, three natural products have been identified, the epothilones, eleutherobin, and discodermolide, whose mechanism of action is similar to that of Taxol in that they stabilize microtubules and block cells in the mitotic phase of the cell cycle. In this report, we have compared and contrasted the effects of these new agents in Taxol-sensitive and -resistant cell lines. We also have taken advantage of a human lung carcinoma cell line, A549-T12, that was isolated as a Taxol-resistant cell line and found to require low concentrations of Taxol (2-6 nM) for normal cell division. This study then examined the ability of these new compounds to substitute for Taxol in sustaining the growth of A549-T12 cells. Immunofluorescence and flow cytometry have both indicated that the epothilones and eleutherobin, but not discodermolide, can substitute for Taxol in this Taxol-dependent cell line. In A549-T12 cells, the presence of Taxol significantly amplified the cytotoxicity of discodermolide, and this phenomenon was not observed in combinations of Taxol with either the epothilones or eleutherobin. Median effect analysis using the combination index method revealed a schedule- independent synergistic interaction between Taxol and discodermolide in four human carcinoma cell lines, an effect that was not observed between Taxol and epothilone B. Flow cytometry revealed that concurrent exposure of A549 cells to Taxol and discodermolide at doses that do not induce mitotic arrest caused an increase in the hypodiploid population, thereby indicating that a possible mechanism for the observed synergy is the potentiation of apoptosis. Our results suggest that Taxol and discodermolide may constitute a promising chemotherapeutic combination.

Original languageEnglish (US)
Pages (from-to)1978-1987
Number of pages10
JournalClinical Cancer Research
Volume6
Issue number5
StatePublished - May 2000

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Drug Combinations
Paclitaxel
Carcinoma
Cell Line
Epothilones
discodermolide
Flow Cytometry
Biological Products
Microtubules
Cell Division
Fluorescent Antibody Technique
Appointments and Schedules
Cell Cycle
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines. / Martello, Laura A.; McDaid, Hayley M.; Regl, Donna Lee; Yang, Chia-Ping H.; Meng, Dongfang; Pettus, Thomas R R; Kaufman, Michael D.; Arimoto, Hirokazu; Danishefsky, Samuel J.; Smith, Amos B.; Band Horwitz, Susan.

In: Clinical Cancer Research, Vol. 6, No. 5, 05.2000, p. 1978-1987.

Research output: Contribution to journalArticle

Martello, LA, McDaid, HM, Regl, DL, Yang, C-PH, Meng, D, Pettus, TRR, Kaufman, MD, Arimoto, H, Danishefsky, SJ, Smith, AB & Band Horwitz, S 2000, 'Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines', Clinical Cancer Research, vol. 6, no. 5, pp. 1978-1987.
Martello, Laura A. ; McDaid, Hayley M. ; Regl, Donna Lee ; Yang, Chia-Ping H. ; Meng, Dongfang ; Pettus, Thomas R R ; Kaufman, Michael D. ; Arimoto, Hirokazu ; Danishefsky, Samuel J. ; Smith, Amos B. ; Band Horwitz, Susan. / Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines. In: Clinical Cancer Research. 2000 ; Vol. 6, No. 5. pp. 1978-1987.
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AU - Meng, Dongfang

AU - Pettus, Thomas R R

AU - Kaufman, Michael D.

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AB - Recently, three natural products have been identified, the epothilones, eleutherobin, and discodermolide, whose mechanism of action is similar to that of Taxol in that they stabilize microtubules and block cells in the mitotic phase of the cell cycle. In this report, we have compared and contrasted the effects of these new agents in Taxol-sensitive and -resistant cell lines. We also have taken advantage of a human lung carcinoma cell line, A549-T12, that was isolated as a Taxol-resistant cell line and found to require low concentrations of Taxol (2-6 nM) for normal cell division. This study then examined the ability of these new compounds to substitute for Taxol in sustaining the growth of A549-T12 cells. Immunofluorescence and flow cytometry have both indicated that the epothilones and eleutherobin, but not discodermolide, can substitute for Taxol in this Taxol-dependent cell line. In A549-T12 cells, the presence of Taxol significantly amplified the cytotoxicity of discodermolide, and this phenomenon was not observed in combinations of Taxol with either the epothilones or eleutherobin. Median effect analysis using the combination index method revealed a schedule- independent synergistic interaction between Taxol and discodermolide in four human carcinoma cell lines, an effect that was not observed between Taxol and epothilone B. Flow cytometry revealed that concurrent exposure of A549 cells to Taxol and discodermolide at doses that do not induce mitotic arrest caused an increase in the hypodiploid population, thereby indicating that a possible mechanism for the observed synergy is the potentiation of apoptosis. Our results suggest that Taxol and discodermolide may constitute a promising chemotherapeutic combination.

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