Nitrogen-containing bisphosphonates inhibit cell cycle progression in human melanoma cells

Abstract

Cutaneous melanoma is one of the highly malignant human tumours, due to its tendency to generate early metastases and its resistance to classical chemotherapy. We recently demonstrated that pamidronate, a nitrogen-containing bisphosphonate, has an antiproliferative and proapoptotic effect on different melanoma cell lines. In the present study, we compared the in vitro effects of three different bisphosphonates on human melanoma cell lines and we demonstrated that the two nitrogen-containing bisphosphonates pamidronate and zoledronate inhibited the proliferation of melanoma cells and induced apoptosis in a dose- and time-dependent manner. Moreover, cell cycle progression was altered, the two compounds causing accumulation of the cells in the S phase of the cycle. In contrast, the nonaminobisphosphonate clodronate had no effect on melanoma cells. These findings suggest a direct antitumoural effect of bisphosphonates on melanoma cells in vitro and further support the hypothesis of different intracellular mechanisms of action for nitrogen-containing and nonaminobisphosphonates. Our data indicate that nitrogen-containing bisphosphonates may be a useful novel therapeutic class for treatment and/or prevention of melanoma metastases.

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

“…It should be noted that cells, exposed up to IC 50 ZOL for 72h, following drug removal later on resume their growth thus indicating the reversibility of the inhibition. In our opinion, this property of ZOL suggests its [23][24][25][26][27]. To date, however, the details of the molecular mechanism of cell cycle arrest involved remain obscure.…”

“…These are required for the posttranslational modification (prenylation) of small GTP proteins (such as Rho, Ras, Rac) that play crucial roles in signaling pathways controlling cell growth. The anti-proliferative effect of ZOL was described in several tumor cell lines and it was likely due to cell cycle distribution change by accumulating and arresting cells in the S-phase [23][24][25][26][27]. This arrest was coupled to changing levels of cyclins and cell cycle regulators, and the S-phase arrest was associated with typical (caspase-dependent) [25,27,28] or atypical (caspase-independent) apoptotic pathway.…”

Anticancer effects of zoledronic acid against human osteosarcoma cells

“…Our observations are in accordance with previously published studies on different types of tumor cells, all suggesting accumulation of ZOL treated cells in S phase. 20,22,23 Kuroda and colleagues 23 reported that ZOL-treated leukemia cells entered apoptosis from the S phase to G2/M boundary. This corresponds with our data demonstrating a distinct loss of G2/M cells at higher ZOL concentrations coinciding with appearance of a sub-G0/G1 peak indicating programmed cell death.…”

Alendronate inhibits cell invasion and MMP-2 secretion in human chondrosarcoma cell line

“…For example, Senaratne et al reported that BP could induce apoptosis in human breast cancer cell lines [17] . Forsea et al also demonstrated that BP had an inhibitory effect in cell cycle progression in human melanoma cells [13] . Furthermore, several studies have demonstrated that alendronate, a BP, could inhibit cell invasion in human epidermoid carcinoma cells [11] and osteosarcoma cells [12] .…”

“…Therefore, the inhibition of migration or invasion mediated by MMP-2 could be a preventive method of cancer metastasis [9] . Recently, there has been increasing evidence indicating that bisphosphonates (BP) have direct antitumor effects in vivo and in vitro, in addition to their therapeutic antiresorptive properties [10][11][12][13][14][15][16][17][18][19] . For example, Senaratne et al reported that BP could induce apoptosis in human breast cancer cell lines [17] .…”