Targeting of Hsp32 in solid tumors and leukemias: a novel approach to optimize anticancer therapy.
Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related anti-apoptotic molecule, that has been implicated in enhanced survival of neoplastic cells and in drug-resistance. We here show that Hsp32 is expressed in most solid tumors and hematopoietic neoplasms and may be employed as a new therapeutic target as evidenced by experiments using specific siRNA and a Hsp32-targeting pharmacologic inhibitor. This Hsp-32 targeting drug, SMA-ZnPP, was found to inhibit the proliferation of neoplastic cells with IC(50) values ranging between 1 and 50 microM. In addition, SMA-ZnPP induced apoptosis in all neoplastic cells examined. Furthermore, SMA-ZnPP was found to synergize with other targeted and conventional drugs in producing growth-inhibition. Resulting synergistic effects were observed in all tumor and leukemia cells examined. Interestingly, several of the drug partners, when applied as single agents, induced the expression of Hsp32 in neoplastic cells, suggesting that synergistic effects resulted from SMA-ZnPP-induced ablation of a Hsp32-mediated survival-pathway that is otherwise used by tumor cells to escape drug-induced apoptosis. Together, Hsp32 is an important survival factor and target in solid tumors and hematopoietic neoplasms, and may be used to optimize anticancer therapy by combining conventional or targeted drugs with Hsp32-inhibitors. Based on these data, it seems desirable to explore the value of Hsp32-targeting drugs as anti-cancer agents in clinical trials.
Gleixner
K V
KV
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, A-1090 Vienna, Austria.
Mayerhofer
M
M
Vales
A
A
Gruze
A
A
Hörmann
G
G
Cerny-Reiterer
S
S
Lackner
E
E
Hadzijusufovic
E
E
Herrmann
H
H
Iyer
A K
AK
Krauth
M-T
MT
Pickl
W F
WF
Marian
B
B
Panzer-Grümayer
R
R
Sillaber
C
C
Maeda
H
H
Zielinski
C
C
Valent
P
P
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology*; D008298:Maleates / Q000494:pharmacology*; D008665:Metalloporphyrins / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D015513:Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology; D011137:Polystyrenes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology
D000970:Antineoplastic Agents; D008298:Maleates; D008665:Metalloporphyrins; D015513:Oncogene Proteins; D011137:Polystyrenes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C518727:copoly(styrene-maleic acid)-zinc protoporphyrin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1