Merrell Melinda A, Wakchoure Savita, Lehenkari Petri P, Harris Kevin W, Selander Katri S
Department of Medicine, Division of Hematology-Oncology, University of Alabama at Birmingham, AL 35294, USA.
Eur J Pharmacol. 2007 Sep 10;570(1-3):27-37. doi: 10.1016/j.ejphar.2007.05.075. Epub 2007 Jun 16.
Bisphosphonates are widely used inhibitors of bone resorption. They also inhibit the growth of various cancer cells in vitro, but the clinical significance of this effect is unclear. The cancer growth inhibitory effects of nitrogen-containing bisphosphonates, (i.e. zoledronate) have been attributed to their ability to inhibit the mevalonate pathway. We have shown that bisphosphonates also induce p38 activation, which signals resistance against the drug-induced growth inhibition through an unknown mechanism. We show here that zoledronate induces a G1/S cell cycle arrest in human MDA-MB-231 breast cancer cells. Furthermore, p38 inhibitor augments bisphosphonate-induced growth inhibition by inducing an additional G2-phase cell cycle arrest. We also show that the nitrogen-containing bisphosphonate-induced effects on p38 phosphorylation occur before accumulation of unprenylated Rap1A or Rac1 activation. Geranylgeranyl pyrophosphate, an end-product of the mevalonate pathway, reversed the accumulation of unprenylated Rap1A but not phosphorylation of p38. Geranylgeranyl pyrophosphate also reversed n-BP induced growth inhibition, but the completeness of this reversal was nitrogen-containing bisphosphonate concentration dependent. Also mevastatin induced the accumulation of unprenylated Rap1A, but it did not induce p38 phosphorylation. In conclusion, our results suggest that in addition to the previously reported effects on apoptosis, nitrogen-containing bisphosphonates also inhibit the growth of MDA-MB-231 breast cancer cells by inducing G1/S cell cycle arrest. The bisphosphonate-induced p38 activation signals for resistance against these drugs, by promoting progression through the G2/M-checkpoint. Of these pathways only growth inhibition is mediated via inhibition of the mevalonate pathway in MDA-MB-231 cells. Combining p38 inhibitors with bisphosphonates may result in increased anti-cancer efficacy.
双膦酸盐是广泛使用的骨吸收抑制剂。它们在体外也能抑制多种癌细胞的生长，但其临床意义尚不清楚。含氮双膦酸盐（如唑来膦酸盐）的抗癌生长作用归因于其抑制甲羟戊酸途径的能力。我们已经表明，双膦酸盐还能诱导p38激活，通过未知机制发出对药物诱导的生长抑制的抗性信号。我们在此表明，唑来膦酸盐在人MDA-MB-231乳腺癌细胞中诱导G1/S细胞周期停滞。此外，p38抑制剂通过诱导额外的G2期细胞周期停滞增强双膦酸盐诱导的生长抑制。我们还表明，含氮双膦酸盐对p38磷酸化的诱导作用发生在未异戊二烯化的Rap1A积累或Rac1激活之前。甲羟戊酸途径的终产物香叶基香叶基焦磷酸可逆转未异戊二烯化的Rap1A的积累，但不能逆转p38的磷酸化。香叶基香叶基焦磷酸也可逆转含氮双膦酸盐诱导的生长抑制，但这种逆转的完全程度取决于含氮双膦酸盐的浓度。此外，美伐他汀诱导未异戊二烯化的Rap1A的积累，但不诱导p38磷酸化。总之，我们的结果表明，除了先前报道的对细胞凋亡的影响外，含氮双膦酸盐还通过诱导G1/S细胞周期停滞抑制MDA-MB-231乳腺癌细胞的生长。双膦酸盐诱导的p38激活通过促进通过G2/M检查点的进程发出对这些药物的抗性信号。在这些途径中，只有生长抑制是通过抑制MDA-MB-231细胞中的甲羟戊酸途径介导的。将p38抑制剂与双膦酸盐联合使用可能会提高抗癌疗效。
