Induction of apoptosis by sulindac sulfide in HL60 cells is enhanced by p21CiP1 or p27KiP1.
The nonsteroidal anti-inflammatory drug (NSAID) sulindac and its derivatives induce apoptosis in a variety of carcinoma cells in vitro and display antitumor effects in vivo. The effects of these agents have not, however, been studied in detail in leukemia cells. In the present study we compared the effects of sulindac sulfide to those of 12-0-tetradecanoylphorbol ester (TPA) on the human promyelocytic leukemia cell line HL60. The latter compound is known to induce monocytic differentiation in these cells. We found that both sulindac sulfide and TPA caused growth inhibition, cell cycle arrest in G0/G1 and increased levels of the cell cycle inhibitory proteins p21Cip1 and p27KiP1. However, whereas the TPA treated cells underwent subsequent differentiation the sulindac sulfide-treated cells displayed extensive apoptosis and negligible differentiation. Ectopic overexpression of p21Cip1 or p27KiP1 markedly enhanced the apoptosis induced by sulindac sulfide. Therefore, sulindac sulfide and related compounds may be useful in the treatment of leukemia and other neoplasms, especially when used together with agents that increase cellular levels of p21Cip1 or p27KiP1.
Ikui
A E
AE
Department of Medicine, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Yao
Y
Y
Zhou
P
P
Weinstein
I B
IB
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis / Q000502:physiology*; D018922:HL-60 Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013467:Sulindac; C025462:sulindac sulfide; D013755:Tetradecanoylphorbol Acetate