Mechanisms of action of flavopiridol

Flavopiridol inhibits phosphokinases. Its activity is strongest on cyclin d ependent kinases (cdk-1, -2, -4, -6, -7) and less on receptor tyrosine kina ses (EGFR), receptor associates tyrosine kinases (pp60 Src) and on signal t ransducing kinases (PKC and Erk-1). Although the inhibiting activity of fla vopiridol is strongest for cdk, the cytotoxic activity of flavopiridol is n ot limited to cycling cells. Resting cells are also killed. This fact sugge sts that inhibition of cdks involved in the control of cell cycle is not th e only mechanism of action. Inhibition of cdk's with additional functions ( i.e. involved in the control of transcription or function of proteins that do not control cell cycle) may contribute to the antitumoral effect. Moreov er, direct and indirect inhibition of receptor activation (EGFR) and/or a d irect inhibition of kinases (pp60 Src, PI(C, Erk-1) involved in the signal transduction pathway could play a role in the antiproliferative activity of flavopiridol. From pharmacokinetic data in patients it can be concluded th at the inhibitory activity (IC50) of flavopiridol on these kinases is in th e range of concentrations that might be achieved intracellularly after syst emic application of non-toxic doses of flavopiridol. However, no in situ da ta from flavopiridol treated cells have been published yet that prove that by inhibition of EGFR, pp60 Src, PKC and/or Erk-1 tin addition to inhibitio n of cdk's) flavopiridol is able to induce apoptosis. Thus many questions r egarding the detailed mechanism of antitumoral action of flavopiridol are s till open. For the design of protocols for future clinical studies this rev iew covers the essential information available on the mechanism of antitumo ral activity of flavopiridol. The characteristics of this antitumoral activ ity include: High rate of apoptosis, especially in leukemic cells; synergy with the antitumoral activity of many cytostatics; independence of its effi cacy on pRb, p53 and Bcl-2 expression; lack of interference with the most f requent multidrug resistance proteins (P-glycoprotein and MRP-190); and a s trong antiangiogenic activity. Based on these pharmacological data it can b e concluded that flavopiridol could be therapeutically active in tumor pati ents: independent on the genetic status of their tumors or leukemias (i.e. mutations of the pRb and/or p53, amplification of bcl-2): in spite of drug resistance of their tumors induced by first line treatment (and caused by e nhanced expression of multidrug resistance proteins); in combination with c onventional chemotherapeutics preferentially given prior to flavopiridol; a nd due to a complex mechanism involving cytotoxicity on cycling and on rest ing tumor cells, apoptosis and antiangiogenic activity. In consequence, fla vopiridol is a highly attractive, new antitumoral compound and deserves fur ther elucidation of its clinical potency. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.