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Adenovirus-mediated FKHRL1/TM sensitizes melanoma cells to apoptosis induced by temozolomide.

Abstract
Melanoma exhibits variable resistance to the alkylating agent temozolomide (TMZ). We evaluated the potential of adenovirus expressing forkhead human transcription factor like 1 triple mutant (Ad-FKHRL1/TM) to sensitize melanoma cells to TMZ. Four melanoma cell lines were treated with Ad-FKHRL1/TM and TMZ, alone or in combination. Apoptosis was assessed by activation and inhibition of caspase pathway, nuclei fragmentation, and annexin V staining. The potential therapeutic efficacy of Ad-FKHRL1/TM with TMZ was also assessed in a mouse melanoma xenograft model. Combination therapy of Ad-FKHRL1/TM and TMZ resulted in greater cell killing (<20% cell viability) compared with single therapy and controls (p<0.05). Combination indices of Ad-FKHRL1/TM and TMZ therapy indicated significant (p<0.05) synergistic killing effect. Greater apoptosis induction was found in cells treated with Ad-FKHRL1/TM and TMZ than with Ad-FKHRL1/TM or TMZ-treated cells alone. Treatment with TMZ enhanced adenovirus transgene expression in a cell type-dependent manner. In an in vivo model, combination therapy of Ad-FKHRL1/TM with TMZ results in greater tumor growth reduction in comparison with single treatments. We suggest that Ad-FKHRL1/TM is a promising vector to sensitize melanoma cells to TMZ, and that a combination of both approaches would be effective in the clinical setting.
AuthorsMichael E Egger, Lacey R McNally, Jonathan Nitz, Kelly M McMasters, Jorge G Gomez-Gutierrez
JournalHuman gene therapy. Clinical development (Hum Gene Ther Clin Dev) Vol. 25 Issue 3 Pg. 186-95 (Sep 2014) ISSN: 2324-8645 [Electronic] United States
PMID25238278 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • FOXO3 protein, human
  • Forkhead Transcription Factors
  • Transcription Factors
  • Dacarbazine
  • temozolomide
Topics
  • Adenoviridae (genetics)
  • Animals
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Dacarbazine (analogs & derivatives, pharmacology)
  • Forkhead Transcription Factors (genetics, metabolism)
  • Genetic Therapy
  • Humans
  • Male
  • Melanoma (therapy)
  • Mice
  • Mice, Inbred BALB C
  • Transcription Factors (genetics, metabolism)
  • Xenograft Model Antitumor Assays

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