Effect of Vinorelbine on cell growth and apoptosis induction in human osteosarcoma in vitro

Abstract

Abstract. Vinorelbine (VNR) is a semi-synthetic vinca alkaloid known to exert its antitumour activity by interfering with the polymerisation of tubulin. It has shown a broad spectrum of activity in some advanced carcinomas of lung, breast and ovary. This report demonstrates for the first time the antiproliferative effect of VNR and its molecular mechanism in human osteosarcoma in vitro. TP53 wild-type HOS cells and TP53 mutated MG-63 cells were chosen for this study. In each cell line, VNR caused a significant dose-and time-dependent growth inhibition and induced apoptotic death independent of TP53 status. Phosphorylation and/or alteration of Bcl-2 were not induced by VNR, thereby indicating a new pathway utilised by the drug to induce apoptosis in this tumour in vitro. VNR produced a down-regulation of cyclin D1 and an upregulation of p53 expression in TP53 wild-type HOS cells, whereas no alteration in cyclin D1 expression was evident in the TP53 negative MG-63 cells. These data suggest a new potential use for Vinorelbine as a therapeutic agent against human osteosarcoma. IntroductionOsteosarcoma (OS) is the most frequent malignant bone tumour with a peak incidence in the second and third decade of life (1). As a result of the introduction of neoadjuvant chemotherapy, an improvement in the long-term survival rate from 10% to nearly 70% has been achieved (2). At present, osteosarcoma patients receive full neoadjuvant multi-agent chemotherapy immediately after diagnosis. Initial tumour size and detectable metastases at diagnosis are prognostic factors and serve together with the response to chemotherapy as a basis for the risk adapted postoperative therapy factor (3,4). Despite the improved survival rate, drug resistance is still one of the major problems in the treatment of this cancer (5). Alterations in the TP53 gene are frequent in human osteosarcoma cells and have been associated with resistance to chemotherapy as well as with poor prognosis in this malignancy (6,7). Pompetti et al (8) correlated TP53 mutations with a lack of therapy-induced apoptosis, while studies by Goto et al (9) demonstrated an association between loss of heterozygosity at TP53 locus and chemoresistance in human osteosarcoma.Different studies indicate that cells lacking a p53 function may present a higher sensitivity to anticancer drugs that induce DNA damage and to the cytotoxic effects of antimicrotubule agents (10-12). Vinorelbine (VNR) is a semisynthetic vinca alkaloid which binds to · and ß tubulin, thus inhibiting microtubule assembly and impairing metaphasic tumour cell division. Compared with different vinca alkaloids, VNR shows markedly improved clinical efficacy and reduced toxicity (13). This drug is now widely used and licensed for the treatment of non-small cell lung cancer, breast cancer and ovarian cancer (14) and shows promise in relapsed or refractory Hodgkin's disease (15) and prostatic carcinoma (16). Like other antimicrotubule agents, VNR is known to be a promoter of apoptosis in cancer cells. The precise mechanism b...

Antitumor Efficacy of Two Novel Non-Thiazolidinedione Compounds as Peroxisome Proliferator-Activated Receptor-γ Agonists in Human Osteosarcoma Cells in vitro

“…ROS = Rosiglitazone. 1 IC 50 values calculated in the group pretreated with 10 M GW9662, which is similar to IC 50 values got without adding it (p > 0.05). …”

“…Although the prognosis of these patients has improved substantially due to the development of neoadjuvant chemotherapy with subsequent surgical resection, 20% of patients still die following tumor metastases [1] . One of the most serious causes of therapeutic failure is the resistance of the tumor cells to currently available chemotherapeutic agents [2] .…”

Metronomic vinorelbine is directly active on Non Small Cell Lung Cancer cells and sensitizes the EGFRL858R/T790M cells to reversible EGFR tyrosine kinase inhibitors

“…Fig. 3B shows the antiproliferative effects of the drug on H-358 cells (IC 50 25.78 ± 2.93 pM), whereas the H-292 cell line was less sensitive to metronomic D-VNR concentrations (IC 50 44.56 ± 1.41 µM), as shown in Fig. 3C.…”

“…In addition, our attention focused on another important mechanism that was previously associated with this vinca alkaloid compound at higher concentrations. Both Sugiyama et al [43] and Roncuzzi et al [44] described a significant downregulation of cyclin-D1 after exposure to standard concentrations of VNR. Similarly, mVNR on NSCLC cells significantly reduced both cyclin-D1 gene expression and protein levels after 144 h of exposure in treated NSCLC cells if compared to controls.…”