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Evaluating combinatorial effects of galbanic acid and arsenic trioxide on ATL cells
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  • Maryam Mahdifar,
  • Mehrdad Iranshahi,
  • Narges Valizadeh,
  • Marzieh Golizadeh,
  • Fatemeh B. Rassouli,
  • Houshang Rafatpanah
Maryam Mahdifar
Mashhad University of Medical Sciences
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Mehrdad Iranshahi
Mashhad University of Medical Sciences
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Narges Valizadeh
Mashhad University of Medical Sciences
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Marzieh Golizadeh
Mashhad University of Medical Sciences
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Fatemeh B. Rassouli
Ferdowsi University of Mashhad
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Houshang Rafatpanah
Mashhad University of Medical Sciences
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Abstract

Abstract Background and Purpose: Galbanic acid (GBA), a sesquiterpene coumarin compound isolated from Ferula species, has noticeable anti-cancer effects. In current research, we investigated effects of GBA in combination with arsenic trioxide (ATO) on MT-2 cells, an Adult T cell leukemia (ATL) cell line. ATL is a malignancy caused by human T cell leukemia virus type 1 (HTLV-1). Experimental Approach: The MT-2 cells were treated with each agent alone at various concentrations. After determination of IC50 values, MT-2 cells were treated with 20 µM GBA combined with 4 µM ATO. The viability of MT-2 cells was evaluated by alamar blue assay and cell cycle distribution was assessed by PI staining. Furthermore, the activity of P-glycoprotein (P-gp) in the presence of GBA was studied by mitoxantrone efflux assay. To understand the molecular mechanisms of GBA+ATO treatment in MT-2 cells, the mRNA expression of RelA, p53, CDK4, c-MYC, c-FLIPL, and c-FLIPS was measured by real-time PCR. Key Results: GBA+ATO synergistically inhibited proliferation of MT-2 cells and induced apoptotic cell death. GBA and ATO also synergized to induce cell cycle arrest with an apparent sub-G1 cells accumulation. Rate of mitoxantrone accumulation in MT-2 cells was enhanced in the presence of GBA, indicating GBA has inhibitory effects on the functionality of the P-gp efflux pump. The real-time PCR analysis revealed that GBA+ATO combination downregulated the expression of p53, CDK4, c-FLIPL, and c-FLIPS. Statistical analysis revealed a significant relation between p53 expression and c-FLIPS. Conclusion and Implications: The GBA+ATO combination could be considered as a new therapeutic approach for ATL patients.