Autophagy

A novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model

Laura A. Lambert, Na Qiao, Kelly K. Hunt, Donald H. Lambert, Gordon Mills, Laurent Meijer, Khandan Keyomarsi

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Doxorubicin is a genotoxic chemotherapy agent used in treatment of a wide variety of cancers. Significant clinical side effects, including cardiac toxicity and myelosuppression, severely limit the therapeutic index of this commonly used agent and methods which improve doxorubicin efficacy could benefit many patients. Because doxorubicin cytotoxicity is cell cycle specific, the cell cycle is a rational target to enhance its efficacy. We examined the direct, cyclin-dependent kinase inhibitor roscovitine as a means of enhancing doxorubicin cytotoxicity. This study showed synergistic cytotoxicity between doxorubicin and roscovitine in three sarcoma cell lines: SW -982 (synovial sarcoma), U2OS-LC3-GFP (osteosarcoma), and SK-LMS-1 (uterine leiomyosarcoma), but not the fibroblast cell line WI38. The combined treatment of doxorubicin and roscovitine was associated with a prolonged G2-M cell cycle arrest in the three sarcoma cell lines. Using three different methods for detecting apoptosis, our results revealed that apoptotic cell death did not account for the synergistic cytotoxicity between doxorubicin and roscovitine. However, morphologic changes observed by light microscopy and increased cytoplasmic LC3-GFP puncta in U20S-LC3-GFP cells after the combined treatment suggested the induction of autophagy. Induction of autophagy was also shown in SW-982 and SK-LMS-1 cells treated with both doxorubicin and roscovitine by acridine orange staining. These results suggest a novel role of autophagy in the enhanced cytotoxicity by cell cycle inhibition after genotoxic injury in tumor cells. Further investigation of this enhanced cytotoxicity as a treatment strategy for sarcomas is warranted.

Original languageEnglish (US)
Pages (from-to)7966-7974
Number of pages9
JournalCancer Research
Volume68
Issue number19
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

Fingerprint

Autophagy
Sarcoma
Doxorubicin
Cell Cycle
Cell Line
G2 Phase Cell Cycle Checkpoints
Synovial Sarcoma
Therapeutics
Acridine Orange
Leiomyosarcoma
Cyclin-Dependent Kinases
roscovitine
Osteosarcoma
Microscopy
Neoplasms
Cell Death
Fibroblasts
Apoptosis
Staining and Labeling
Light

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Autophagy : A novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model. / Lambert, Laura A.; Qiao, Na; Hunt, Kelly K.; Lambert, Donald H.; Mills, Gordon; Meijer, Laurent; Keyomarsi, Khandan.

In: Cancer Research, Vol. 68, No. 19, 01.10.2008, p. 7966-7974.

Research output: Contribution to journalArticle

Lambert, Laura A. ; Qiao, Na ; Hunt, Kelly K. ; Lambert, Donald H. ; Mills, Gordon ; Meijer, Laurent ; Keyomarsi, Khandan. / Autophagy : A novel mechanism of synergistic cytotoxicity between doxorubicin and roscovitine in a sarcoma model. In: Cancer Research. 2008 ; Vol. 68, No. 19. pp. 7966-7974.
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