Inhibition of Chondrosarcoma Growth by mTOR Inhibitor in an In Vivo Syngeneic Rat Model

Abstract

BackgroundChondrosarcomas are the second most frequent primary malignant type of bone tumor. No effective systemic treatment has been identified in advanced or adjuvant phases for chondrosarcoma. The aim of the present study was to determine the antitumor effects of doxorubicin and everolimus, an mTOR inhibitor on chondrosarcoma progression.Methods and FindingsDoxorubin and/or everolimus were tested in vivo as single agent or in combination in the rat orthotopic Schwarm chondrosarcoma model, in macroscopic phase, as well as with microscopic residual disease. Response to everolimus and/or doxorubicin was evaluated using chondrosarcoma volume evolution (MRI). Histological response was evaluated with % of tumor necrosis, tumor proliferation index, metabolism quantification analysis between the treated and control groups. Statistical analyses were performed using chi square, Fishers exact test. Doxorubicin single agent has no effect of tumor growth as compared to no treatment; conversely, everolimus single agent significantly inhibited tumor progression in macroscopic tumors with no synergistic additive effect with doxorubicin. Everolimus inhibited chondrosarcoma proliferation as evaluated by Ki67 expression did not induce the apoptosis of tumor cells; everolimus reduced Glut1 and 4EBP1 expression. Importantly when given in rats with microscopic residual diseases, in a pseudo neoadjuvant setting, following R1 resection of the implanted tumor, everolimus significantly delayed or prevented tumor recurrence.ConclusionsMTOR inhibitor everolimus blocks cell proliferation, Glut1 expression and HIF1a expression, and prevents in vivo chondrosarcoma tumor progression in both macroscopic and in adjuvant phase post R1 resection. Taken together, our preclinical data indicate that mTOR inhibitor may be effective as a single agent in treating chondrosarcoma patients. A clinical trial evaluating mTOr inhibitor as neo-adjuvant and adjuvant therapy in chondrosarcoma patients is being constructed.

Targeting glucose metabolism in chondrosarcoma cells enhances the sensitivity to doxorubicin through the inhibition of lactate dehydrogenase-A

“…Cells were seeded in 12-well plates at 1x10 5 -3x10 5 cells/well. Culture media was collected at 48 h and stored at -20˚C until assayed.…”

“…Currently, chondrosarcomas are relatively chemotherapy-and radiotherapy-resistant. A recent study reported that the growth of chondrosarcoma cells can be inhibited by mTOR inhibitor in an in vivo syngeneic rat model (5), suggesting a putative chemotherapeutic approach for clinical applications. Doxorubicin (Dox) is an antitumor drug that is used frequently in chemotherapy for a variety of solid tumors (6).…”

Metabolic stress and cancer: is autophagy the common denominator and a feasible target?

“…[34] In support of these previous findings was the data from an experimental study in an in vivo chondrosarcoma model. [37] There was also found to be an increase in Akt activation and is proposed to be a result of the negative feedback loop. [37] Interestingly, these observations were only found in the DOX treatment group, [37] and thus, it is postulated that DOX is inducing a response similar to that stimulated by hypoxia [23] (Figure 3, Table 2).…”

“…[37] There was also found to be an increase in Akt activation and is proposed to be a result of the negative feedback loop. [37] Interestingly, these observations were only found in the DOX treatment group, [37] and thus, it is postulated that DOX is inducing a response similar to that stimulated by hypoxia [23] (Figure 3, Table 2). The literature has focused on the feasibility of mTOR inhibitors as a primary adjuvant therapy or in combination with other chemotherapeutics.…”

“…It is proposed that enhanced AMPK activation induces the activation of Bim and apoptosis. Here, there may lie another switching mechanism from autophagy to apoptosis involving a key regulator and would lend to the theory that there is no one molecule responsible for the switch between autophagy to apoptosis but that many key regulators of various autophagic pathways have the ability [27] PUMA Deleted Induces Bax/Bak-dependent autophagy [28] DAPK Deleted Phosphorylation of Beclin-1 at Thr-119 disassociates Bcl-xl [29] HMGB1 Amplified Disassociates Bcl-2 from Beclin-1 [30] SIRT1 Amplified Activation of the LKB1-AMPK pathway Involved in autophagosome formation [31][32][33][34] Akt Amplified Inhibition through mTOR activation Increases nutrient availability [35][36][37] AMBRA1 Amplified Biogenesis of the autophagosome membrane [38] MUC-1 Amplified Increases activation of AMPK [39] PARP-1 Amplified Activation of AMPK [26,[40][41][42][43] LKB1 Deleted Activation of AMPK [5,6,11] FOXO3A Amplified Inhibition through Akt [12] AMBRA1, activating molecule in Beclin-1-regulated autophagy; AMPK, adenosine monophosphate kinase; LKB1 = liver kinase B1; mTOR, mammalian target of rapamycin.…”