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Anticancer Agents Med Chem. 2019 Jul 31. doi: 10.2174/1871520619666190731155859. [Epub ahead of print]

Kaempferol Improves TRAIL-Mediated Apoptosis in Leukemia MOLT-4 Cells by the Inhibition of Anti-Apoptotic Proteins and Promotion of Death Receptors Expression

Author information

1
Immunology research Center, Tabriz University of Medical Sciences, Tabriz, Iran
2
Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3
Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

INTRODUCTION:

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily, which stimulates apoptosis in a wide range of cancer cells via binding to death receptors 4 and 5 (DR4/5). Nevertheless, TRAIL has noticeable anti-cancer abilities; some cancer cells acquire resistance to TRAIL, and consequently its potential for inducing apoptosis in target cells is strongly diminished. Acute lymphoblastic leukemia MOLT-4 cell line is one of the most resistant cells to TRAIL that developed resistance to TRAIL via different pathways. We used TRAIL plus kaempferol to eliminate resistance of the MOLT-4 cells to TRAIL.

MATERIAL AND METHODS:

First, IC50 for kaempferol (95 µM) was determined by using the MTT assay. Second, the viability of the MOLT-4 cells was assayed by FACS after Annexin V/PI staining, following treatment with TRAIL (50 and 100 nM) and kaempferol (95 µM) alone and together. Finally, the expression levels of the candidate genes involved in resistance to TRAIL were assayed by real-time PCR technique.

RESULTS:

Kaempferol plus TRAIL induced apoptosis robustly in MOLT-4 cells at 12, 24 and 48 hours after treatment. Additionally, we found that kaempferol could inhibit expression of the c-FLIP, X-IAP, cIAP1/2, FGF-8 and VEGF-beta, and conversely augment expression of the DR4/5 in MOLT-4 cells.

CONCLUSION:

We suggest that co-treatment of MOLT-4 cells with TRAIL plus kaempferol is a practical and attractive approach to eliminate cancers' resistance to TRAIL via inhibition of the intracellular anti-apoptotic proteins, upregulation of DR4/5 and also by suppression of the VEGF-beta (VEGFB) and FGF-8 expressions.

KEYWORDS:

Acute lymphoblastic leukemia (ALL); MOLT-4; kaempferol; resistance and TRAIL

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