Relationship of Drug Sensitivity and Expression of hypoxia-inducible factor-1 (HIF-1)

2002 Fiscal Year Final Research Report Summary

• Project/Area Number: 13671044
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: HOKKAIDO UNIVERSITY
• Principal Investigator: HASHINO Satoshi Hokkaido Univ. Grad. School of Med., Assist. Prof., 医学部附属病院, 講師 (60271665)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Masanobu Inst. For Genetic Med., Hokakido University, Assoc. Prof., 遺伝子病制御研究所, 助教授 (80241321)
• Project Period (FY): 2001 – 2002
• Keywords: Taxol / apoptosis / MyD88 / NF-κB / TNF-α / signal transduction

Research Abstract

We have studied the sensitivity of several leukemia cell lines to anti-cancer drugs. We have noticed that some myelomonocytic leukemia cell lines are sensitive to low concentrations of Taxol. Myelomonocytic leukemia cell lines are more sensitive to Taxol than ovary cancer cell lines. We have examined the mechanisms how myelomonocytic leukemia cell lines are sensitive to low doses of Taxol. According to the previous reports demonstrating that Taxol transduced the signal through the activation of MyD88 and NF-κB and then induced the expression of TNF-α mRNA in murine macrophages and that Taxol induced the expression of TNF-α mRNA in human cancer cells through the activation of NF-κB, we hypothesized that Taxol also transduced the signals through the activation of MyD88 in human macrophages. We first examined the activation of NF-κB and the expression of TNFα mRNA after incubaing human myelomonocytic leukemia cell lines with 10 nM Taxol. We found that Taxol induced the activation of NF-κB and the expression of TNF-α mRNA in human myelomonocytic leukemia cell lines at 10 nM. Then we next established the cell lines transfected with dominant negative MyD88 (dnMyD88). In the dnMyD88-transfectants, taxol did not induce the activation of NF-κB or the expression of TNF-αRNA. In those cells, we examined the induction of apoptosis after treatment with 10 nM Taxol. Taxol induced apoptosis in about 50 % of the vector-control cells and in 20-30 % of the dnMyD88-transfectants. These results suggest that Taxol-induced apoptosis was transduced through the activation of MyD88 and that Taxol may be useful for the treatment with myelomonocytic leukemia.

Research Products

• [Publications] J.Wang, S.Hashino, et al.: "MyD88 is involved in the signalling pathway for Taxol-induced apoptosis and TNF-α expression in human myelomonocytic cells"British Journal of Haematology. 118. 638-645 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] J.Chen, M.Kobayashi, et al.: "Dominant negative HIF-1 α reduces tumorigenicity of pancreatic cancer cells through the suppression of hypoxia-inducible anaerobic metabolism"American Journal of Pathology. 162. 1283-1291 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Wang J, Kobayashi M. Han M, Choi S, Takano M, Hashino S. Tanaka J, Kondoh T, Kawamura K, Hosokawa M.: "MyD88 is involved in signaling pathway for Taxol-induced apoptosis and TNF-・ expression in human myelomonocytic cells"Br J. Haematol.. 118. 638-645 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Chen J, Kobayashi M, Akakura N, Zhao S, Nakada K, Kuge Y, Tamaki N, Wang J, Shindo M, Higashino F, Seth P, Hosokawa M.: "Dominant negative HIF-1・reduces tumorigenicity of pancreatic cancer cell through the suppression of hypoxia-inducible anaerobic metabolism"Am. J Pathol.. 162. 1283-1291 (2003)
  • Description: 「研究成果報告書概要(欧文)」より