Zheng Xi, Ryan Amanda, Patel Namrata, Klemons Stephanie, Hansson Annette, Shih Weichung Joe, Lin Yong, Huberman Eliezer, Chang Richard L, Conney Allan H
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Int J Oncol. 2005 Feb;26(2):441-8.
Our previous studies demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) had pharmacological activity for the treatment of myeloid leukemia patients. In the present study, we investigated the effects of TPA alone or in combination with capsaicin (8-methyl-N-vanillyl-6-nonenamide) on growth and differentiation in myeloid leukemia HL-60 cells and in a TPA-resistant HL-60 variant cell line termed HL-525. Treatment of HL-60 cells with TPA (0.16-1.6 nM) for 48 h resulted in concentration-dependent growth inhibition and cell differentiation (via the macrophage pathway). Capsaicin (5-50 microM) inhibited the growth of HL-60 cells in a concentration-dependent manner. Treatment of HL-60 cells with capsaicin alone only resulted in a small increase in the number of differentiated cells but treatment of the cells with TPA in combination with capsaicin synergistically increased differentiation. Moreover, inhibitors of protein kinase C (PKC), 7-hydroxystaurosporin (UCN-01; 100 nM) and chelerythrine (0.5 microM), significantly decreased HL-60 cell differentiation induced by the combination of TPA and capsaicin. These results suggest that PKC may be involved in HL-60 cell differentiation induced by TPA in combination with capsaicin. Capsaicin alone caused a very small increase in differentiation in the TPA-resistant HL-525 cells. However, treatment of HL-525 cells with combinations of TPA (0.16 nM) and capsaicin (10-50 microM) caused a strong synergistic increase in differentiation. Results from the present study suggest that a combination of TPA and capsaicin may improve the therapeutic efficacy of TPA and overcome resistance to TPA in some myeloid leukemia patients.
我们之前的研究表明，12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）对治疗髓系白血病患者具有药理活性。在本研究中，我们研究了单独使用TPA或其与辣椒素（8 - 甲基 - N - 香草基 - 6 - 壬烯酰胺）联合使用对髓系白血病HL - 60细胞以及一种称为HL - 525的TPA耐药HL - 60变异细胞系生长和分化的影响。用TPA（0.16 - 1.6 nM）处理HL - 60细胞48小时导致浓度依赖性生长抑制和细胞分化（通过巨噬细胞途径）。辣椒素（5 - 50 microM）以浓度依赖性方式抑制HL - 60细胞的生长。单独用辣椒素处理HL - 60细胞仅导致分化细胞数量略有增加，但用TPA与辣椒素联合处理细胞则协同增加分化。此外，蛋白激酶C（PKC）抑制剂7 - 羟基星孢菌素（UCN - 01；100 nM）和白屈菜红碱（0.5 microM）显著降低了TPA和辣椒素联合诱导的HL - 60细胞分化。这些结果表明PKC可能参与了TPA与辣椒素联合诱导的HL - 60细胞分化。单独使用辣椒素仅使TPA耐药的HL - 525细胞分化略有增加。然而，用TPA（0.16 nM）和辣椒素（10 - 50 microM）联合处理HL - 525细胞导致分化强烈协同增加。本研究结果表明，TPA与辣椒素联合使用可能提高TPA的治疗效果，并克服部分髓系白血病患者对TPA的耐药性。
