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

• DOI: 10.1158/1078-0432.c.6523610.v1
• Publication Date: 2023-04-01T06:40:23Z
• Authors: Irina A. Vasilevs...; Muthu Selvakumaran; Lucia Cabal Hierro; Sara R. Goldstein; Jeffrey D. Winkler; Peter J. O'Dwyer
• Keywords: Hypoxia

<div>Abstract<p><b>Purpose:</b> We showed previously that in HT29 colon cancer cells, modulation of hypoxia-induced stress signaling affects oxaliplatin cytotoxicity. To further study the significance through JNK, we set out to investigate how kinase activities influences cellular responses hypoxic cells cytotoxic drugs.</p><p><b>Experimental Design:</b> In a panel cell lines, investigated effects pharmacologic and molecular inhibition JNK on sensitivity oxaliplatin, SN-38, 5-FU. Combination studies for drugs inhibitor CC-401 were carried <i>in vitro</i> vivo</i>.</p><p><b>Results:</b> Hypoxia-induced activation was associated with resistance oxaliplatin. combination chemotherapy demonstrates synergism although synergy is not always hypoxia specific. A more detailed analysis focused SW620 (responsive), HCT116 (nonresponsive) lines. treatment results greater DNA damage sensitive cells. <i>In vivo</i>, potentiation bevacizumab, by confirmed HT29-derived mouse xenografts, which tumor growth delay presence CC-401. Finally, stable introduction dominant negative JNK1, but JNK2, construct into rendered them under hypoxia, suggesting differing input isoforms chemotherapy.</p><p><b>Conclusions:</b> These findings demonstrate determinant response therapy models, support testing sensitize tumors clinic. <i>Clin Cancer Res; 21(18); 4143–52. ©2015 AACR</i>.</p></div>