Herbimycin A accelerates the induction of apoptosis following etoposide treatment or γ-irradiation of bcr/abl-positive leukaemia cells

Abstract

Philadelphia chromosome (Ph)-positive leukaemia cells express the chimeric bcr/abl oncoprotein, whose deregulated protein tyrosine kinase (PTK) activity antagonizes the induction of apoptosis by DNA damaging agents. Treatment of Ph-positive K562, TOM 1 and KCL-22 cells with etoposide for 2d induced cytosolic vacuolation, but not nuclear condensation or DNA fragmentation. The bcr/abl kinase-selective inhibitor herbimycin A increased the induction of nuclear apoptosis by etoposide or g-radiation. The concentration of herbimycin required to synergize with etoposide was similar to that required to decrease the level of tyrosine phosphorylated proteins or of the protein tyrosine kinase activity of anti-abl immune complexes in K562 cells. The ability of herbimycin A to sensitize K562, TOM 1 or KCL-22 cells to apoptosis induction correlated with its ability to decrease the cellular content of phosphotyrosyl proteins in these Philadelphia-positive lines. Enhancement of nuclear apoptosis by herbimycin was not attributable to downregulation of the bcl-2 or bcl-X L anti-apoptotic proteins. In contrast, herbimycin protected Philadelphianegative HL60 cells from apoptosis induction by etoposide and did not a ect killing of NC37 and CEM cells. The data suggest that the induction of apoptosis is blocked in cells expressing the bcr/abl oncoprotein and that herbimycin A increases induction of programmed cell death following DNA damage. Selective PTK inhibitors may therefore be of value in securing the genetic death of Ph-positive leukaemia cells.

Protein Kinase Cι Activity Is Necessary for Bcr-Abl-mediated Resistance to Drug-induced Apoptosis

“…Our results with PKC are reminiscent of those described previously for Bcr-Abl, whose expression and tyrosine kinase activity is required for resistance of K562 cells to drug-induced apoptosis (5,10,(11)(12)(13)(14)(15). Indeed, although both HL60 and K562 cells express similar levels of PKC, the pattern of PKC activity in these cells during apoptotic stress is distinct.…”

“…The Bcr-Abl gene is the transforming activity responsible for CML (9), and the resistance of K562 cells to drug-induced apoptosis is conferred by Bcr-Abl (5,10,11). Thus, inhibition of Bcr-Abl tyrosine kinase activity using selective inhibitors (12)(13)(14)(15) or of Bcr-Abl expression using antisense oligonucleotides (16,17) leads to increased sensitivity of K562 cells to apoptosis induced by many drugs including taxol.…”

A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells

“…39,40 Also because of the activation of the PI3K/Akt pathway, K562 cells are resistant to multiple apoptosis inducers. [41][42][43] As expected, K562 were found by immunoblotting to express high levels of Thr 308 p-Akt, which were effectively downregulated by treatment with either Ly294002 or Akt inhibitor (Figure 9a). K562 cells were resistant to etoposide, cytarabine, TRAIL, and irradiation.…”

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).…”