Combined inhibition of Hsp90 and heme oxygenase-1 induces apoptosis and endoplasmic reticulum stress in melanoma.
Heat shock proteins are ubiquitous molecular chaperones involved in post-translational folding, stability, activation and maturation of many proteins that are essential mediators of signal transduction and cell cycle progression. Heat shock protein 90 (Hsp90) has recently emerged as an attractive therapeutic target in cancer treatment since it may act as a key regulator of various oncogene products and cell-signaling molecules. Heme oxygenase-1 (HO-1; also known as Hsp32) is an inducible enzyme participating in heme degradation and involved in oxidative stress resistance. Recent studies indicate that HO-1 activation may play a role in tumor development and progression. In the present study we investigated the chemotherapic effects of combining an Hsp90 inhibitor (NMS E973) and an HO-1 inhibitor (SnMP) on A375 melanoma cells. NMS E973 treatment was able to reduce cell viability and induce endoplasmic reticulum (ER) stress (i.e. Ire1α, ERO1, PDI, BIP and CHOP). Interestingly, no significant effect was observed in reactive oxygen species (ROS) formation. Finally, NMS E973 treatment resulted in a significant HO-1 overexpression, which in turn serves as a possible chemoresistance molecular mechanism. Interestingly, the combination of NMS E973 and SnMP produced an increase of ROS and reduced cell viability compared to NMS E973 treatment alone. The inhibitors combination exhibited higher ER stress, apoptosis as evidenced by bifunctional apoptosis regulator (BFAR) mRNA expression and lower phosphorylation of Akt when compared to NMS E973 alone. In conclusion, these data suggest that HO-1 inhibition potentiates NMS E973 toxicity and may be exploited as a strategy for melanoma treatment.
Department of Drug Sciences, University of Catania, Via Andrea Doria 6, 95125 Catania, Italy; EuroMediterranean Institute of Science and Technology, Via Emerico Amari 123, 90139 Palermo, Italy.
Ignazio
I
Barbagallo
Department of Biomedical and Biotechnological Sciences, University of Catania, Via Andrea Doria 6, 95125 Catania, Italy.
Rosalba
R
Parenti
Department of Biomedical and Biotechnological Sciences, University of Catania, Via Andrea Doria 6, 95125 Catania, Italy.
Agata
A
Zappalà
Department of Drug Sciences, University of Catania, Via Andrea Doria 6, 95125 Catania, Italy.
Luca
L
Vanella
Division of Hematology, AOU "Policlinico-Vittorio Emauele", University of Catania, Via Santa Sofia 78, 95125 Catania, Italy.
Daniele
D
Tibullo
Department of Biomedical Sciences, Section of Physiology, University of Catania, Via Andrea Doria 6, 95125 Italy.
Francesco
F
Pepe
Department of Biomedical Sciences, Section of Physiology, University of Catania, Via Andrea Doria 6, 95125 Italy.
Toniangelo
T
Onni
Department of Biomedical and Biotechnological Sciences, University of Catania, Via Andrea Doria 6, 95125 Catania, Italy; EuroMediterranean Institute of Science and Technology, Via Emerico Amari 123, 90139 Palermo, Italy. Electronic address: livolti@unict.it.
Giovanni
G
Li Volti
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D008665:Metalloporphyrins; C585926:NMS-E973; D017382:Reactive Oxygen Species; C055421:tin mesoporphyrin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
Apoptosis; Cancer; ER stress; Heme oxygenase; Hsp90; Melanoma