Notch pathway inhibition using DAPT, a γ-secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma.

Overcoming platinum drug resistance represents a major clinical challenge in osteosarcoma (OS) treatment. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). Notch signaling is implicated in regulating CSCs and tumor resistance to platinum. Thus, we attempt to investigate whether inhibiting of Notch pathway could sensitize cisplatin (CDDP) to CDDP-resistant OS cells and the underlying molecular mechanisms. OS cell lines resistant to CDDP were treated with DAPT, CDDP or combination, we present evidences that DAPT enhances the cytotoxic effect of CDDP in resistant OS by inhibiting proliferation, resulting in G0/G1 cell-cycle arrest, inducing apoptosis, and reducing motility. In addition, DAPT targeting depletes OS stem cells (OSCs), thus increasing tumor sensitivity to platinum, which indicating that a dual combination targeting both OSCs and the bulk of tumor cells are needed for tumor eradication. We also found that the combination of CDDP and DAPT exhibit additive suppression on phosphorylated AKT and ERK, contributing to the anti-cancer effects. In animal model, this combination therapy inhibits the growth and metastasis of CDDP resistant tumor xenografts in nude mice to a greater extent than treatment with either reagent alone. Based on these results, we conclude that CDDP plus DAPT was able to sensitize CDDP-resistant human OS cells to CDDP by downregulation of Notch signaling. CDDP and DAPT combination treatment may be effective and promising for advanced OS.

Dai G ，Deng S ，Guo W ，Yu L ，Yang J ，Zhou S ，Gao T ... -  《-》

Suppressing CHD1L reduces the proliferation and chemoresistance in osteosarcoma.

Osteosarcoma (OS) is the most common bone malignant tumor. However, the genetic basis of OS pathogenesis is still not understood, and occurrence of chemo-resistance is a major reason for the high morbidity of OS patients. Recently, chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) has been identified as a gene related to malignant tumor progression. Unfortunately, its effects on OS development and drug resistance are still not understood. In the study, we attempted to investigate the effects of CHD1L on tumorigenesis and chemoresistance in OS. We found that CHD1L expression was markedly up-regulated in OS samples, especially in cisplatin (cDDP)-resistant patients. We also showed that OS cells with CHD1L knockdown were more sensitive to cDDP treatment with lower IC50 values. In addition, we found that CHD1L deletion markedly reduced cell proliferation and induced apoptosis in OS cells with cDDP resistance. Moreover, the properties of cancer stem cells were highly suppressed in cDDP-resistant OS cells following CHD1L knockdown. Furthermore, multidrug resistance protein 1 (MDR-1) expression levels were dramatically decreased in OS cells with cDDP resistance when CHD1L was suppressed. Functional analysis indicated that CHD1L knockdown clearly restrained the activation of ERK1/2, protein kinase B (AKT) and NF-κB signaling pathways in cDDP-resistant OS cells. Consistently, animal experiments suggested that CHD1L suppression mitigated cDDP resistance in the generated in vivo xenografts. Collectively, CHD1L could modulate chemoresistance of OS cells to cDDP, and thus may be inspiring findings for overcoming drug resistance in OS.

Fan GT ，Ling ZH ，He ZW ，Wu SJ ，Zhou GX ... -  《-》

Pretreatment with the γ-secretase inhibitor DAPT sensitizes drug-resistant ovarian cancer cells to cisplatin by downregulation of Notch signaling.

Wang M ，Ma X ，Wang J ，Wang L ，Wang Y ... -  《-》

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model.

Cisplatinum (CDDP) is a first-line drug in osteosarcoma treatment and the acquisition of resistance to CDDP is associated with a poor prognosis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that plays important roles in cell proliferation, differentiation, development, metabolism and cell death. Recently, PPARγ was reported to enhance the efficacy, overcome resistance, and decrease the toxicity of CDDP in various human cancers. In this study we tested whether pioglitazone (PIO), a PPARγ agonist, could overcome CDDP resistance in osteosarcoma. In this study, we used a human osteosarcoma cell line and a patient-derived orthotopic xenograft (PDOX) models of osteosarcoma. We measured cell viability of 143B human osteosarcoma cells when treated with CDDP and PIO. We randomized PDOX models of osteosarcoma into four treatment groups: Group 1, Untreated control; Group 2, PIO alone; Group 3, CDDP alone; Group 4, a combination of CDDP and PIO. Each group comprised six mice. Mice were treated for 14 days and tumor size and body weight were measured. Cell viability of 143B human osteosarcoma cells was significantly reduced when PIO (50 μmol/l) was combined with CDDP compared to CDDP alone. PDOX osteosarcoma tumors treated with the CDDP-PIO combination showed the strongest tumor growth inhibition compared to other treatment groups. PDOX osteosarcoma tumors treated with the CDDP-PIO combination had the least cancer cells and the most necrosis in histological section. These results suggest that combining PIO along with CDDP could be an effective treatment strategy for osteosarcoma and has important clinical potential for patients.

Higuchi T ，Yamamoto J ，Sugisawa N ，Tashiro Y ，Nishino H ，Yamamoto N ，Hayashi K ，Kimura H ，Miwa S ，Igarashi K ，Bouvet M ，Singh SR ，Tsuchiya H ，Hoffman RM ... -  《-》

Inhibition of the Notch signaling pathway attenuates progression of cell motility, metastasis, and epithelial-to-mesenchymal transition-like phenomena induced by low concentrations of cisplatin in osteosarcoma.

Although advances in osteosarcoma treatment have been made in recent decades, the survival rate for patients suffering from metastatic disease, especially lung metastasis, remains disappointing. Previous studies have confirmed that epithelial-to-mesenchymal transition (EMT) is associated with tumor metastasis, and several studies have suggested that osteosarcoma cells also exhibit EMT-like characteristics. In addition, Notch signaling is known to be related to the development and progression of human malignancies, including osteosarcoma. However, whether chemotherapy affects the EMT-like events and whether these events are medicated by Notch signaling remain to be elucidated. To address these issues, in the current work, osteosarcoma 143B cells were exposed to sublethal concentrations of the first-line chemotherapeutic agent cisplatin (DDP), which promoted cell migration, in vitro invasion, and in vivo lung metastasis. Furthermore, low concentrations of DDP upregulated mesenchymal phenotype-related genes and proteins and promoted EMT-like properties in osteosarcoma cells. In addition, low concentrations of DDP could activate the Notch receptor and its target genes. Finally, combined treatment of DDP with the Notch signaling pathway inhibitor DAPT, which can effectively downregulate mesenchymal phenotype-related genes and proteins, inhibited cell migration and invasion in vitro, and it decreased pulmonary metastatic nodules in vivo. The results of the current study supported the idea that low concentrations of DDP could induce EMT-like characteristics in osteosarcoma cells and could promote cell mobility in vitro, as well as pulmonary metastasis in vivo. Importantly, however, these biological processes are mediated by the Notch signaling pathway. Blocking the Notch signaling pathway can effectively attenuate the osteosarcoma EMT-like phenotype and its associated migration, invasion, and metastasis.

Dai G ，Liu G ，Zheng D ，Song Q ... -  《-》