Eradication of glioblastoma, and breast and colon carcinoma xenografts by Hsp70 depletion.
Heat shock protein 70 (Hsp70) is an antiapoptotic chaperone protein highly expressed in human tumors. Here we demonstrate that locoregional application of adenovirus expressing antisense Hsp70 cDNA (Ad.asHsp70) eradicates orthotopic xenografts of glioblastoma and breast carcinoma, as well as s.c. xenografts of colon carcinoma in immunodeficient mice. Ad.asHsp70-treated tumors showed massive apoptosis-like cell death and recruitment of macrophages. Human monocyte-derived macrophages effectively removed the corpses of Ad.asHsp70-treated tumor cells in vitro. Interestingly, both tumor cell death and phagocytosis were caspase-independent. Thus, Hsp70 appears as a promising target for the treatment of cancers resistant to classic caspase-mediated apoptosis.
Nylandsted
Jesper
J
Apoptosis Laboratory, Institute for Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark.
Wick
Wolfgang
W
Hirt
Ulrich A
UA
Brand
Karsten
K
Rohde
Mikkel
M
Leist
Marcel
M
Weller
Michael
M
Jäättelä
Marja
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016373:DNA, Antisense / Q000235:genetics / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018840:HSP70 Heat-Shock Proteins / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010587:Phagocytosis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D016373:DNA, Antisense; D018840:HSP70 Heat-Shock Proteins