Background: Cytokeratins hold potential as biomarkers due to their epithelial specificity, abundance and cleavage by caspases during apoptosis. We evaluated paclitaxel-induced circulating caspase-cleaved (cc) cytokeratin 18 (CK18) as potential apoptotic cell-death marker to guide treatment optimization in ovarian cancer.
Methods: Six ovarian cancer cell lines (SK-OV-3, SK-OV-3lucIP1, Caov-3, NIH:OVCAR-3, PA-1 and PM-LGSOC-01) were exposed in vitro to paclitaxel (PTX, 0 to 1000 nM) for 24h. Extracellular levels of ccCK18 were measured until 5 days after drug exposure. Cell count and ccCK18 release data were analyzed using a phase-nonspecific pharmacodynamic model implemented in NONMEM®. PA-1 and SK-OV-3lucIP1 xenografted female SCID/Beige mice received a placebo or single dose of 50 mg/kg PTX intraperitoneally. Response to PTX was evaluated in vivo using tumor volume and released ccCK18 levels.
Results: In vitro, the correlation between cell count and released ccCK18 levels was present in all cell lines (Spearman’s rank correlation coefficient > 0.64). Tumor volume and ccCK18 longitudinal dynamics were markedly different for controls and PTX-treated PA-1 xenografts with changes in ccCK18 release preceding changes in tumor volume. For SK-OV-3lucIP1 xenografts, no differences were found between controls and PTX-treated mice.
Conclusions: An association between PTX-induced ccCK18 release and cell count was demonstrated in vitro. The in vivo study supported the presence of an early-apoptotic peak in ccCK18 levels compared to a later observed effect on tumor volume in PTX-sensitive xenografts. Given the heterogeneous character of ovarian cancer, application and implementation of ccCK18 in a clinical setting to optimize or personalize cancer treatment needs further refinement.