Bisphosphonates (BPs) are widely used in the treatment of osteolytic bone disease associated with multiple myeloma, and have been demonstrated to exert antitumor effects both in vitro and in vivo. However, the precise molecular mechanisms involved in the direct antitumor effects of BPs in vitro are not known. Nitrogen-containing BPs, such as risedronate (RIS), act by inhibiting protein prenylation. A phosphonocarboxylate analogue of RIS, 3-PEHPC, has previously been shown in osteoclasts and macrophages to specifically inhibit prenylation of Rab GTPases. The aim of this study was to identify the molecular targets of RIS and 3-PEHPC in human myeloma cells and to determine the cellular effects of selective inhibition of Rab prenylation by 3-PEHPC as compared to nonspecific inhibition of protein prenylation by RIS in human myeloma cells. RIS dose-dependently inhibited prenylation of both Rap1A and Rab6, whereas 3-PEHPC only inhibited Rab6 prenylation. Both RIS and 3-PEHPC dose-dependently increased apoptosis in human myeloma cells. RIS induced an accumulation of cells in the S-phase of the cell cycle, associated with inhibition of DNA replication. In contrast, 3-PEHPC did not cause cell-cycle arrest. Furthermore, geranylgeraniol could prevent inhibition of prenylation, induction of apoptosis, and cell-cycle arrest in response to RIS, but not inhibition of Rab prenylation and apoptosis induced by 3-PEHPC, consistent with specific inhibition of Rab geranylgeranyl transferase by 3-PEHPC. In conclusion, our studies demonstrate that selective inhibition of Rab prenylation induces apoptosis, but not S-phase arrest, thus identifying distinct molecular pathways that mediate the antimyeloma effect of nitrogen-containing BPs. © 2006 Wiley-Liss, Inc.
Introduction Around 25% of metastatic breast cancer (mBC) patients develop brain metastases, which vastly affects their overall survival and quality of life. According to the current clinical guidelines, regular magnetic resonance imaging screening is not recommended unless patients have recognized central nervous system-related symptoms. Patient Presentation The patient participated in the EFFECT study, a randomized controlled trial aimed to assess the effects of a 9-month structured, individualized and supervised exercise intervention on quality of life, fatigue and other cancer and treatment-related side effects in patients with mBC. She attended the training sessions regularly and was supervised by the same trainer throughout the exercise program. In month 7 of participation, her exercise trainer detected subtle symptoms (e.g., changes in movement pattern, eye movement or balance), which had not been noticed or reported by the patient herself or her family, and which were unlikely to have been detected by the oncologist or other health care providers at that point since symptoms were exercise related. When suspicion of brain metastases was brought to the attention of the oncologist by the exercise trainer, the response was immediate, and led to early detection and treatment of brain metastases. Conclusion and clinical implications The brain metastases of this patient were detected earlier due to the recognition of subtle symptoms detected by her exercise trainer and the trust and rapid action by the clinician. The implementation of physical exercise programs for cancer patients requires well-trained professionals who know how to recognize possible alterations in patients and also, good communication between trainers and the medical team to enable the necessary actions to be taken.
