Late apoptotic effects of taxanes on K562 erythroleukemia cells: Apoptosis is delayed upstream of caspase‐3 activation

Abstract

The efficacy of taxanes on human leukemia cells is the object of intensive in vitro investigation concerning the influence of cell‐type‐specific characteristics on cytotoxic response to drugs. The present study dissects the response to taxanes of HL60 acute myelomonocytic leukemia and of K562 chronic myelogenous leukemia, in parallel over a 72‐hr time‐span. The kinetics of cytotoxicity following pulsed and continuous exposure to either taxol or taxotere showed a delayed response of K562 cells independently of dose and type of exposure. In K562 cells, apoptosis became evident at 48 hr and prominent at 72 hr of treatment. These events were mirrored by delayed kinetics of caspase‐3 activation. Comparable microtubule targeting was demonstrated in HL60 and in K562 cell lines, as bcl‐2 and raf‐1 were phosphorylated following treatment with taxanes. These observations indicate that early activation processes were responsible for apoptosis, but that the delay was determined by other factors. In addition, cell‐free‐system experiments excluded the presence of excess nuclear and/or cytoplasmic inhibitory factors and demonstrated that K562 cells possess a fully competent caspase system which can be readily activated. Processing of caspase‐3 pro‐enzyme was in fact increased by addition of cytochrome c. These results extend to taxol and taxotere the notion that drug‐induced apoptosis is delayed upstream of caspase‐3 activation in K562 cells, that such kinetics is independent of drug concentration and exposure time, and that it is linked to intrinsic cellular characteristics mapping between bcl‐2 phosphorylation and cytochrome c release. Int. J. Cancer 85:527–533, 2000. © 2000 Wiley‐Liss, Inc.

Different regulatory pathways are involved in the proliferative inhibition of two types of leukemia cell lines induced by paclitaxel

“…Our present results showed the dose-and time-dependency of the antitumor effects of paclitaxel on these two types of leukemia cells, and the potency of paclitaxel in K562 cells was stronger than in MEL cells. Paclitaxel clearly induced apoptosis in K562 cells, which is in accordance with previous results (21). Also, there was a significant arrest of cell cycle to G 2 /M phase induced by paclitaxel in K562 cells, similar to the findings of a previous report (26).…”

“…Previous studies showed the efficacy of taxanes on human leukemic cell lines (16,(19)(20)(21), as well as their effectiveness in inducing apoptosis in vivo (22) and in fresh leukemia cells in primary cultures (23). However, to the best of our knowledge, there is no report on the effect of paclitaxel on leukemia induced by virus.…”

8-Chloro-Cyclic AMP–Induced Growth Inhibition and Apoptosis Is Mediated by p38 Mitogen-Activated Protein Kinase Activation in HL60 Cells

“…However, in K562 cells, which are tolerable to many apoptosis-inducing agents, p38 MAPK was not activated and apoptotic cell death was not observed after 8-Cl-cAMP treatment. The mechanisms by which the BCR-ABL-positive leukemia cells resist the apoptotic signals are not fully understood, although delayed caspase activation or increased Bcl-X L level in K562 cells has been reported (32). We showed here that p38 MAPK activation can be regarded as another determinant to execute apoptosis in leukemia cells.…”

“…However, K562 (chronic myelogenous leukemia) was more resistant to the growth inhibitory effect of 8-Cl-cAMP than HL60. It has been reported that K562 cells express the BCR-ABL fusion protein due to genetic rearrangement that maintains resistance to apoptosis induced under various conditions (31,32).…”

Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection

“…Thus, HL60 cells undergo apoptosis in response to chemotherapeutic agents with diverse mechanisms of action: doxorubicin (DOX) and etoposide (topoisomease-II inhibitors), paclitaxel (PTX; microtubule active agent), flavopiridol (FL; an inhibitor of transcription) and proteasomal inhibitors. [1][2][3][4][5][6] In contrast, apoptosis-reluctant cells, including common cancer cell lines, undergo either slow (nonapoptotic) types of cell death or cycle arrest. 7 For example, K562 leukemia cells are apoptosis reluctant, because they express the Bcr-Abl antiapoptotic kinase, which in turn induces heat-shock protein-70 (Hsp70).…”