Synergistic stimulatory effect of 12-O-tetradecanoylphorbol-13-acetate and capsaicin on macrophage differentiation in HL-60 and HL-525 human myeloid leukemia cells.
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.
Zheng
Xi
X
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.
Ryan
Amanda
A
Patel
Namrata
N
Klemons
Stephanie
S
Hansson
Annette
A
Shih
Weichung Joe
WJ
Lin
Yong
Y
Huberman
Eliezer
E
Chang
Richard L
RL
Conney
Allan H
AH
D000470:Alkaloids; D000970:Antineoplastic Agents / Q000494:pharmacology; D053119:Benzophenanthridines; D002211:Capsaicin / Q000494:pharmacology*; D043182:Carboxylesterase / Q000378:metabolism; D002273:Carcinogens; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008956:Models, Chemical; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013997:Time Factors
D000470:Alkaloids; D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D002273:Carcinogens; D004791:Enzyme Inhibitors; D010617:Phenanthridines; C054852:7-hydroxystaurosporine; C016299:chelerythrine; D011493:Protein Kinase C; D043182:Carboxylesterase; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D002211:Capsaicin