Effect of casein kinase 2 (CK2) inhibitors on antitumor activity of cisplatin in an isogenic pair of sensitive and resistant ovarian tumor cell lines Free

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Wild-type p53 is found in about 40% of ovarian cancers that are clinically refractory to platinum-based therapy, and this is counter-intuitive based on the central apoptotic role of this tumor suppressor. We have reported that in such cancers, wild-type p53 induced by cisplatin is unable to transactivate p21, which may be the molecular mechanism responsible for the resistance phenotype. Literature reports suggest that expression of the protein kinase CK2 may downregulate p21 expression, and, therefore, the possibility was explored that inhibitors of CK2 may restore cisplatin sensitivity by facilitating p21 induction. In our studies, we used sensitive A2780 ovarian tumor cells and its isogenic cisplatin-resistant 2780CP model that demonstrated an IC₅₀ by MTT for cisplatin of ~0.2 µM and ~10 µM, respectively. In contrast, 2780CP cells demonstrated a reduced level of cross-resistance to the CK2 inhibitors DRB (5,6-dichloro-1-β-D-ribofuranosylbenzimidazole; IC₅₀: A2780, 3.7 µM vs. 2780CP, 9.6 µM) and emodin (2.2 vs. 3.6 µM). When A2780 cells were pre-treated with DRB at an IC₁₀ level (1 µM), and then exposed to cisplatin 24 h later for MTT analysis following a 5-day continuous exposure, the IC₅₀ of cisplatin surprisingly was increased at least 2-fold. A similar upward shift in IC₅₀ of cisplatin by DRB (5 µM) or emodin (3 µM) was also observed in 2780CP cells, and this demonstrated that the increased resistance was unrelated to initial cisplatin sensitivity or cell context. In studies to examine scheduling effects, simultaneous exposure of 2780CP cells to cisplatin and emodin also increased the IC₅₀ of cisplatin when compared to cisplatin alone (17 vs 10 μM), but if these cells were pre-exposed to an IC₁₀ level of emodin for 24 hr and washed before exposure to cisplatin, or if exposure to emodin was delayed 24 hr after adding cisplatin to cell cultures, then the IC₅₀ of cisplatin remained unchanged (8.7 vs 9.3 μM; 7.8 vs 8.8 μM). Thus, our results demonstrate that, contrary to expectations, CK2 inhibitors DRB and emodin increase resistance to cisplatin, and, therefore, caution needs to be exercised when combining these inhibitors with this platinum drug. The possibility raised from scheduling studies that this increased resistance is due to interference by the inhibitors of cellular cisplatin uptake is being examined. Thus, it is possible that more specific and potent inhibitors of CK2 may be required to examine the concept of a viable combination with cisplatin to overcome resistance.