Vinblastine Induces Acute, Cell Cycle Phase–Independent Apoptosis in Some Leukemias and Lymphomas and Can Induce Acute Apoptosis in Others when Mcl-1 Is Suppressed

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BlankVinblastine Induces Acute, Cell Cycle Phase–Independent Apoptosis in Some

Leukemias and Lymphomas and Can Induce Acute Apoptosis in Others when Mcl-1 Is

Suppressed

1.. Bethany L. Salerni1,

2.. Darcy J. Bates1,

3.. Tina C. Albershardt1,

4.. H. Lowrey2 and

5.. Alan Eastman1

+ Author Affiliations

1.. Authors' Affiliations: Departments of 1Pharmacology and Toxicology and

2Medicine, and 3Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon,

New Hampshire

1.. Corresponding Author:

Alan Eastman, Norris Cotton Cancer Center, Rubin Building Level 6, Dartmouth

Medical School, Lebanon, NH 03756. Phone: 603-653-9981; Fax: 603-653-9952.

E-mail: Alan.R.Eastman@...

Abstract

Chemotherapeutic agents modify intracellular signaling that culminates in the

inhibition of Bcl-2 family members and initiates apoptosis. Inhibition of the

extracellular signal-regulated kinase by PD98059 dramatically accelerates

vinblastine-mediated apoptosis in ML-1 leukemia with cells dying in 4 hours from

all phases of the cell cycle. Inhibition of protein synthesis by cycloheximide

also markedly accelerated vinblastine-induced apoptosis, showing that the

proteins required for this acute apoptosis are constitutively expressed.

Vinblastine induced the rapid induction of Mcl-1 that was inhibited by PD98059

and cycloheximide. No change in Bcl-2 or Bcl-X was observed. We hypothesize that

ML-1 cells use Mcl-1 for protection from the rapid vinblastine-induced

apoptosis. This was confirmed by targeting Mcl-1 with short hairpin RNA. We also

investigated the response of 13 other leukemia and lymphoma cell lines and cells

from seven chronic lymphocytic leukemia patients. Four cell lines and all

chronic lymphocytic leukemia cells were killed in 6 hours by vinblastine alone.

Two additional cell lines were sensitized to vinblastine by PD98059, which

suppressed Mcl-1. This acute apoptosis either alone or in combination with

PD98059 required vinblastine-mediated activation of c-Jun-NH2-terminal kinase.

PD98059 did not suppress Mcl-1 in other cell lines whereas sorafenib did, but

this did not sensitize the cells to vinblastine, suggesting that the acute

apoptosis varies depending on which Bcl-2 protein mediates protection. Most of

the cell lines were sensitized to vinblastine by cycloheximide, suggesting that

inhibition of a short-lived protein in addition to Mcl-1 can acutely sensitize

cells. These results suggest several clinical strategies that might provide an

effective therapy for selected patients. Mol Cancer Ther; 9(4); 791–802. ©2010

AACR.

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