Pharmacology unit, Department of Cancer Biology, National, Cancer Institute, Cairo University, Fom El-Khalig, Cairo, Egypt.
Toxicol Appl Pharmacol. 2011 Sep 15;255(3):271-86. doi: 10.1016/j.taap.2011.06.019. Epub 2011 Jul 1.
Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide±celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule.
塞来昔布是环氧化酶-2 的抑制剂，目前正在癌症临床试验中研究其增强化疗疗效的作用。本研究调查了环氧化酶-2 抑制剂使不同来源的细胞对几种化疗药物敏感的能力。还研究了药物作用机制和给药顺序的影响。分析了不同孵育方案下五种不同癌细胞系（HeLa、HCT116、HepG2、MCF7 和 U251）对 5-FU、顺铂、阿霉素和依托泊苷±塞来昔布的敏感性、细胞周期、细胞凋亡和 DNA 损伤。我们发现，在所有孵育方案中，MCF7 乳腺癌细胞中塞来昔布与四种药物之间存在拮抗作用，除两种 HCT116 细胞组合外，塞来昔布与多柔比星在所有细胞系中均存在拮抗作用。在其余四种细胞系中，塞来昔布与其他三种药物的组合产生了不同的相互作用。机制研究表明，塞来昔布在不同细胞中产生不同的分子作用。在一些细胞系中，它可消除药物诱导的 G2/M 期阻滞，促进有损伤的 DNA 提前进入有丝分裂，从而增加细胞凋亡，导致协同作用。在其他细胞中，它增强了药物诱导的 G2/M 期阻滞，允许在进入有丝分裂之前有时间修复药物诱导的 DNA 损伤，减少细胞死亡，从而导致拮抗作用。在一些协同组合中，塞来昔布诱导的 G2/M 期阻滞的消除与细胞凋亡无关，而是与 G1 期的永久性阻滞有关。如果这些结果在体内得到证实，表明塞来昔布不适合作为乳腺癌的化疗增敏剂，也不适合与多柔比星联合用于其他癌症。此外，塞来昔布与其他药物的联合应用应根据肿瘤类型、药物和给药方案进行调整。
