Inhibition of JNK Sensitizes Hypoxic Colon Cancer Cells to DNA-Damaging Agents.

Abstract

PURPOSE:

We showed previously that in HT29 colon cancer cells, modulation of hypoxia-induced stress signaling affects oxaliplatin cytotoxicity. To further study the significance of hypoxia-induced signaling through JNK, we set out to investigate how modulation of kinase activities influences cellular responses of hypoxic colon cancer cells to cytotoxic drugs.

EXPERIMENTAL DESIGN:

In a panel of cell lines, we investigated effects of pharmacologic and molecular inhibition of JNK on sensitivity to oxaliplatin, SN-38, and 5-FU. Combination studies for the drugs and JNK inhibitor CC-401 were carried out in vitro and in vivo.

RESULTS:

Hypoxia-induced JNK activation was associated with resistance to oxaliplatin. CC-401 in combination with chemotherapy demonstrates synergism in colon cancer cell lines, although synergy is not always hypoxia specific. A more detailed analysis focused on HT29 and SW620 (responsive), and HCT116 (nonresponsive) lines. In HT29 and SW620 cells, CC-401 treatment results in greater DNA damage in the sensitive cells. In vivo, potentiation of bevacizumab, oxaliplatin, and the combination by JNK inhibition was confirmed in HT29-derived mouse xenografts, in which tumor growth delay was greater in the presence of CC-401. Finally, stable introduction of a dominant negative JNK1, but not JNK2, construct into HT29 cells rendered them more sensitive to oxaliplatin under hypoxia, suggesting differing input of JNK isoforms in cellular responses to chemotherapy.

CONCLUSIONS:

These findings demonstrate that signaling through JNK is a determinant of response to therapy in colon cancer models, and support the testing of JNK inhibition to sensitize colon tumors in the clinic.

• Authors: Irina A Vasilevskaya, Muthu Selvakumaran, Lucia Cabal Hierro, Sara R Goldstein, Jeffrey D Winkler, Peter J O'Dwyer
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 18 Pg. 4143-52 (Sep 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 26023085 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Organoplatinum Compounds
• Protein Kinase Inhibitors
• Oxaliplatin
• Irinotecan
• Mitogen-Activated Protein Kinase 8
• Fluorouracil
• Camptothecin

Topics

• Angiogenesis Inhibitors (chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Camptothecin (administration & dosage, analogs & derivatives)
• Cell Hypoxia
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy)
• DNA Damage (drug effects)
• Down-Regulation
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Female
• Fluorouracil (administration & dosage)
• Genes, Dominant
• HT29 Cells
• Humans
• Immunohistochemistry
• Irinotecan
• Mice
• Mice, SCID
• Mitogen-Activated Protein Kinase 8 (antagonists & inhibitors, genetics)
• Organoplatinum Compounds (administration & dosage)
• Oxaliplatin
• Protein Kinase Inhibitors (chemistry)
• Transfection
• Xenograft Model Antitumor Assays