Dihydroflavonol BB-1, an extract of natural plant Blumea balsamifera, abrogates TRAIL resistance in leukemia cells

Blood. 2006 Jan 15;107(2):679-88. doi: 10.1182/blood-2005-05-1982. Epub 2005 Sep 29.


Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells but not in normal cells and, hence, has emerged as a novel anticancer agent. Previously, we showed that although most adult T-cell leukemia/lymphoma (ATLL) cells express the TRAIL death receptor DR4 (TRAIL-R1) or DR5 (TRAIL-R2), they are resistant to TRAIL. Thus, in this study, we tried to find natural products that can overcome TRAIL resistance. Among more than 150 materials screened, a dihydroflavonol that was extracted from Blumea balsamifera (BB-1) exhibited the most striking synergism with TRAIL. Treatment of the TRAIL-resistant ATLL cell line KOB, with a combination of BB-1 and TRAIL, resulted in apparent apoptosis that was not observed on treatment with either agent alone. Furthermore, pretreatment with BB-1 followed by TRAIL further augmented the synergism. BB-1 increased the level of TRAIL-R2 promoter activity and surface protein expression in a p53-independent manner. TRAIL-R2 siRNA inhibited the synergism, indicating that sensitization was caused by the increase of TRAIL-R2 expression. More interestingly, similar effects were observed in other leukemia cell lines by exactly the same mechanisms. These results suggest that combined treatment with BB-1 and TRAIL may be a new strategy for cancer therapy.

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / therapeutic use*
  • Asteraceae / chemistry*
  • Drug Resistance, Neoplasm*
  • Drug Synergism
  • Drug Therapy, Combination
  • Flavonols / isolation & purification
  • Flavonols / therapeutic use*
  • Humans
  • Leukemia / drug therapy*
  • Leukemia-Lymphoma, Adult T-Cell
  • Membrane Glycoproteins / therapeutic use*
  • Plant Extracts / therapeutic use
  • Promoter Regions, Genetic / genetics
  • RNA, Small Interfering / pharmacology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction / drug effects
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / therapeutic use*
  • Tumor Suppressor Protein p53 / metabolism


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Flavonols
  • Membrane Glycoproteins
  • Plant Extracts
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53