RESUMEN
The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for many cancers with little known in osteosarcoma. This study evaluated the efficacy of eFT508, a highly selective inhibitor of MNK1/2, as single drug alone and in combination with paclitaxel in preclinical models of osteosarcoma. EFT508 is active against multiple osteosarcoma cell lines via inhibiting growth, survival and migration. It also demonstrates anti-osteosarcoma selectivity with much less toxicity on normal osteoblastic than osteosarcoma cells. Consistent with in vitro findings, eFT508 at non-toxic dose significantly arrested tumor growth in mice throughout the whole duration of treatment. Mechanistically, eEFT508 is highly effective in blocking eIF4E phosphorylation and eIF4E-mediated protein translation. Combination index shows that eFT508 and paclitaxel is synergistic in osteosarcoma cells. Our findings highlight the therapeutic value of MNK1/2 inhibition and suggest eFT508 as a promising candidate for the treatment of osteosarcoma.
Asunto(s)
Neoplasias Óseas , Resistencia a Antineoplásicos , Osteosarcoma , Animales , Ratones , Línea Celular Tumoral , Factor 4E Eucariótico de Iniciación/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Paclitaxel , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
Considering the increased resistance to antibiotics in the clinic and the ideal antibacterial properties of KR12, the effects of KR12a6, an important analogue of KR12, on the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) were investigated. Osteogenic differentiationassociated experiments were conducted in hBMSCs, and KR12a6 was used as an additional stimulating factor during osteogenic induction. Quantitative analysis of alkaline phosphatase (ALP) and alizarin red staining, and reverse transcriptionquantitative PCR analysis of the expression of osteogenesisassociated genes were performed to determine the effects of KR12a6 on the osteogenic differentiation of hBMSCs. LDN212854 was selected to selectively suppress BMP/SMAD signaling. Western blotting was performed to investigate the underlying mechanisms. The intensity of ALP and alizarin red staining gradually increased with increasing KR12a6 concentrations. KR12a6 induced the strongest staining at 40 µg/ml, whereas 60 µg/ml and 80 µg/ml concentrations did not further increase the intensity of staining. The mRNA expression levels of RUNX2 and ALP increased in a dosedependent manner as early as 3 days postKR12a6 treatment. The mRNA expression of COL1A1, BSP and BMP2 exhibited significant upregulation from day 7 postKR12a6 treatment. In contrast, the mRNA levels of OSX, OCN and OPN were enhanced dramatically at day 14 following KR12a6 stimulation. Additionally, KR12a6 significantly promoted the phosphorylation of Smad1/5. Furthermore, LDN212854 suppressed the activation of Smad1/5 and inhibited the upregulation of several osteogenic differentiationassociated genes in KR12a6treated hBMSCs. KR12a6 promoted the osteogenic differentiation of hBMSCs via BMP/SMAD signaling.
