In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates

Abstract

In a double blind randomized study, the bisphosphonate drug Pamidronate (Aredia) significantly protected Durie-Salmon stage III multiple myeloma patients from osteolytic bone disease. In the patient sub-group on salvage chemotherapy. Pamidronate treatment was also significantly associated with prolonged survival. To test if this drug could induce direct antitumor effects, we exposed myeloma cells to increasing concentrations of Pamidronate or a more potent bisphosphonate, Zoledronate. A concentration-and time-dependent cytotoxic effect was detected on four of five myeloma cell lines as well as three specimens obtained directly from myeloma patients. Zoledronate-induced cytotoxicity was significantly greater than that of Pamidronate. Cytotoxicity could not be explained by bisphosphonate-induced chelation of extracellular calcium or secondary decrease in production of the myeloma growth factor interleukin-6. Morphological examination, DNA electrophoresis and cell cycle analysis indicated that the bisphosphonate-induced cytotoxic effect consisted of a combination of cytostasis and apoptotic myeloma cell death. Enforced expression of BCL-2 protected against the apoptotic death but not against cytostasis. Most cytotoxic effects were seen between 10 and 100 M of drug. The results suggest a possible direct anti-tumor effect in myeloma patients treated with bisphosphonates which may participate in their significantly increased survival. This hypothesis should now be further tested in clinical trials.

The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel

“…These observations are consistent with previous studies that have demonstrated that bisphosphonates cause a significant reduction in osteoclast number (Hughes et al, 1995;Fisher et al, 1999). Importantly, studies in human myeloma cells have shown that nitrogen-containing bisphosphonates, including zoledronic acid, also inhibit cell proliferation (Shipman et al, 1997(Shipman et al, , 1998Aparicio et al, 1998;Derenne et al, 1999). The effects of zoledronic acid on MCF-7 and MDA-MB-231 cell number were associated with concomitant dose-and time-dependent changes in nuclear morphology that were characteristic of apoptosis (Wyllie et al, 1980).…”

“…bisphosphonates such as pamidronate, incadronate, and zoledronic acid (Hughes et al, 1995;Rogers et al, 1996;Shipman et al, 1997Shipman et al, , 1998Aparicio et al, 1998;Fisher et al, 1999). Although there were significant differences between the levels of apoptosis detected by the 2 different techniques, the relative changes induced by bisphosphonate treatment were similar.…”

Zoledronic acid determines S-phase arrest but fails to induce apoptosis in cholangiocarcinoma cells

“…A few years ago it was reported that the enhanced Bcl-2 expression alters the threshold for apoptosis in a cholangiocarcinoma cell line [52]. Moreover, Bcl-2 over-expression could protect myeloma cells against ZOL-induced apoptosis but not against cytostasis [53]. In agreement with this report, our results show that Bcl-xL, an antiapoptotic member of the Bcl-2 family proteins, is significantly expressed in both cholangiocarcinoma cell lines, while the pro-apoptotic Bax protein is largely expressed only in TFK-1 cells.…”

Advances in the use of bisphosphonates in the prostate cancer setting

“…They have been shown to inhibit cell proliferation and viability, and induce apoptosis in a number of cancer cell lines, including prostate cancer. [33][34][35][36][37] Work in our centre with breast cancer cells provided early evidence that inhibition of the mevalonate pathway was again central to the Bisphosphonates in the prostate cancer setting JP Coxon et al observed apoptotic effects. 38 We recently published similar results for various prostate cancer cell lines, 35 and provided evidence that the resultant apoptosis was dependent on the activation of caspases.…”