Heat shock proteins and acute leukemias.
Heat shock proteins (HSPs) acts as molecular chaperones by helping in the refolding of misfolded proteins and assisting in their elimination if they become irreversibly damaged. HSPs induced by stress treatment have a role in the modulation of apoptosis. The reduction in protein expression levels was correlated with an increased susceptibility to drug-induced apoptosis. HSPs have also been implicated in the resistance of leukemia cells to potential therapeutic agents. The mechanisms of cellular protection used by HSPs have yet to be fully defined. HSPs were shown highly expressed by acute myeloid leukemia (AML) cells as well as by acute lymphoblastic leukemia (ALL) cells. HSP expressions were correlated with that of differentiation antigens and that of drug-resistance and apoptosis proteins. Complete remission (CR) rates were higher in patients with lower expression of HSPs. Overall survival (OS) was significantly longer in patients with lower expression of HSPs. Therapeutically, inhibition of inducible HSP expression or activity should not cause any undesired side effects. HSPs emerge as novel therapeutic targets in anticancer protocols. Early results of phase I studies indicate that 17-allylamino-17-demethoxygeldamycin (17-AAG), capable of binding and disrupting the function of HSP90, results in an acceptable toxicity profile while achieving in vivo disruption of multiple oncogenic client proteins.
Thomas
Xavier
X
Département d'Hématologie, Hôpital Edouard Herriot, Lyon, France. xavier.thomas@chu-lyon.fr
Campos
Lydia
L
Le
Quoc-Hung
QH
Guyotat
Denis
D
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones; D017321:Clinical Trials, Phase I as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; D017828:Rifabutin; C112765:tanespimycin