Received for publication September 4, 2007.
Revised February 18, 2008.
Accepted for publication February 19, 2008.

Flavopiridol Suppresses TNF-Induced Activation of AP-1, JNK, p38 MAPK, p44/p42 MAPK and Akt, Inhibits Expression of Antiapoptotic Gene Products, and Enhances Apoptosis Through Cytochrome c Release and Caspase Activation in Human Myeloid Cells

Abstract

Although flavopiridol, a semisynthetic flavone, was initially thought to be a specific inhibitor of cyclin-dependent kinases, it has now been shown that flavopiridol mediates antitumor responses through mechanism(s) yet to be defined. Previously, we have shown that flavopiridol abrogates TNF-induced NF-B activation. In this report, we examined whether this flavone affects other cellular responses activated by TNF. TNF is a potent inducer of activator protein (AP)-1, and flavopiridol abrogated this activation in a dose- and time-dependent manner. Flavopiridol also suppressed AP-1 activation induced by various carcinogens and inflammatory stimuli. When examined for its effect on other signaling pathways, flavopiridol inhibited TNF-induced activation of various mitogen-activated protein kinases, including JNK, p38 MAPK, and p44/p42 MAPK. Interestingly, this flavone also suppressed TNF-induced activation of Akt, a cell survival kinase and expression of various antiapoptotic proteins such as, IAP-1, IAP-2, XIAP, Bcl-2, Bcl-xL, and TRAF-1. Flavopiridol also inhibited the TNF-induced induction of ICAM-1, c-Myc, and c-Fos, all known to mediate tumorigenesis. Moreover, TNF-induced apoptosis was enhanced by flavopiridol through activation of the bid-cytochrome-caspase-9-caspase-3 pathway. Overall, our results clearly suggest that flavopiridol interferes with the TNF cell-signaling pathway, leading to suppression of antiapoptotic mechanisms and enhancement of apoptosis.

Key words: Tumor necrosis factor, MAP Kinase, Jun Kinase, P38 MAP Kinase, AP-1, Mechanisms of cell killing/apoptosis, Transcription targets