Comparative Study of 17-AAG and NVP-AUY922 in Pancreatic and Colorectal Cancer Cells: Are There Common Determinants of Sensitivity?
The use of heat shock protein 90 (Hsp90) inhibitors is an attractive antineoplastic therapy. We wanted to compare the effects of the benzoquinone 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) and the novel isoxazole resorcinol-based Hsp90 inhibitor NVP-AUY922 in a panel of pancreatic and colorectal carcinoma cell lines and in colorectal primary cultures derived from tumors excised to patients. PANC-1, CFPAC-1, and Caco-2 cells were intrinsically resistant to 17-AAG but sensitive to NVP-AUY922. Other cellular models were sensitive to both inhibitors. Human epidermal growth factor receptor receptors and their downstream signaling pathways were downregulated in susceptible cellular models, and concurrently, Hsp70 was induced. Intrinsic resistance to 17-AAG did not correlate with expression of ATP-binding cassette transporters involved in multidrug resistance. Some 17-AAG-resistant, NVP-AUY922-sensitive cell lines lacked
quinone oxidoreductase 1 (NQO1) enzyme and activity. However, colorectal LoVo cells still responded to both drugs in spite of having undetectable levels and activity of NQO1. Pharmacological and biologic inhibition of NQO1 did not confer resistance to 17-AAG in sensitive cell lines. Therefore, even though 17-AAG sensitivity is related to NQO1 protein levels and enzymatic activity, the absence of NQO1 does not necessarily convey resistance to 17-AAG in these cellular models. Moreover, NVP-AUY922 does not require NQO1 for its action and is a more potent inhibitor than 17-AAG in these cells. More importantly, we show in this report that NVP-AUY922 potentiates the inhibitory effects of chemotherapeutic agents, such as gemcitabine or oxaliplatin, and other drugs that are currently being evaluated in clinical trials as antitumor agents.
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain.
Leticia
L
Mayor-López
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain.
Elena
E
Tristante
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain.
Mar
M
Carballo-Santana
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Alicante, Spain.
Estefanía
E
Carrasco-García
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Alicante, Spain.
Silvina
S
Grasso
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Alicante, Spain ; Unidad de Investigación, Hospital General Universitario de Elche, 03203 Elche, Alicante, Spain.
Pilar
P
García-Morales
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Alicante, Spain ; Unidad de Investigación, Hospital General Universitario de Elche, 03203 Elche, Alicante, Spain.
Miguel
M
Saceda
Servicio de Cirugía, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain.
Juan
J
Luján
Servicio de Anatomía Patológica, Hospital General Universitario Santa Lucía, 30202 Cartagena, Murcia, Spain.
José
J
García-Solano
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain ; Servicio de Gastroenterología, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain.
Fernando
F
Carballo
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain.
Carlos
C
de Torre
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria, 30120 Murcia, Spain ; Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Alicante, Spain.
Isabel
I
Martínez-Lacaci