Dual targeting Bcl-2 and Bcl-xL augments osteosarcoma response to doxorubicin.

Chemotherapy resistance is the major cause of treatment failure in osteosarcoma, the most common primary bone malignancy, and sensitizing therapeutic strategy is required to improve the clinical outcome. In this study, we discovered that navitoclax, a selective inhibitor of Bcl-2/Bcl-xL, effectively combats chemoresistance in osteosarcoma. Our research revealed that Bcl-2, but not Bcl-xL, is upregulated in osteosarcoma cells that are resistant to doxorubicin. However, venetoclax, a specific inhibitor of Bcl-2, did not exhibit activity against doxorubicin-resistant cells. Further analysis showed that depleting either Bcl-2 or Bcl-xL alone was insufficient to overcome doxorubicin resistance. Only by depleting both Bcl-2 and Bcl-xL significantly reduce the viability of doxorubicin-resistant cells. Similarly, navitoclax not only decreased the viability of doxorubicin-resistant cells but also acted synergistically with doxorubicin in cells sensitive to the drug. To confirm the ability of navitoclax to overcome doxorubicin resistance, we conducted experiments using multiple mouse models of osteosarcoma, both doxorubicin-sensitive and doxorubicin-resistant. The results provided confirmation that navitoclax is effective in overcoming doxorubicin resistance. Our findings demonstrate that simultaneous inhibition of Bcl-2 and Bcl-xL could serve as a novel strategy to sensitize chemoresistant osteosarcoma cells. Moreover, our study presents preclinical evidence supporting the potential of a navitoclax and doxorubicin combination therapy for the treatment of osteosarcoma, paving the way for future clinical investigations.

LncRNA SNHG10 is downregulated in non-small cell lung cancer and predicts poor survival.

BACKGROUND: LncRNA SNHG10 has been reported to be an oncogenic lncRNA in liver cancer. However, its roles in non-small cell lung cancer (NSCLC) remains unknown. METHODS: Tumor and paired non-tumor tissues were harvested from 62 NSCLC patients. RT-qPCR was used to detect the expression of SNHG10 and miR-21 in tissues. Overexpression experiments were used to evaluate the interaction between SNHG10 and miR-21 in NSCLC cells. CCK-8 assay was used to detect the cell proliferation. RESULTS: We observed the expression of SNHG10 was down-regulated in non-small cell lung cancer (NSCLC) compared with that in non-tumor tissues. Moreover, we found that high expression levels of SNHG10 predicted favorable survival of NSCLC patients, and the expression of miR-21 were increased in NSCLC and inversely correlated with SNHG10 expression. In NSCLC cells, overexpression of SNHG10 resulted in increased miR-21 gene methylation and decreased miR-21 expression. Moreover, overexpression of SNHG10 attenuated the enhancing effect of miR-21 overexpression on cell proliferation. CONCLUSIONS: SNHG10 may involve in NSCLC cell proliferation by regulating the miR-21 gene methylation.

MicroRNA-25 contributes to cisplatin resistance in gastric cancer cells by inhibiting forkhead box O3a.

Gastric cancer (GC) is a common type of malignancy worldwide, and chemotherapeutic resistance accounts for the majority of the failures in clinical treatment. MicroRNAs (miRs) are a class of small non-coding RNAs, which serve essential roles in GC. The present study aimed to investigate the potential role of miR-25 in the cisplatin sensitivity of GC cells. The expression level of miR-25 was significantly upregulated in the cisplatin-resistant GC cell line SGC-7901/DDP compared with the SGC-7901 parental cell line. Overexpression of miR-25 significantly enhanced cell cycle progression and decreased the sensitivity of SGC-7901 cells to cisplatin, whereas inhibition of miR-25 in the SGC-7901/DDP cisplatin-resistant cells resulted in cell cycle arrest at the G0/G1 phase and significantly increased drug sensitivity. Furthermore, the tumor suppressor forkhead box O3a (FOXO3a) was identified as a direct target gene of miR-25 by luciferase assay and western blot analysis, and was shown to mediate the drug-resistance phenotype of GC cells. These findings suggest that upregulation of miR-25 is important for GC cells to establish a cisplatin-resistant phenotype via a FOXO3a-dependent mechanism. Therefore, targeting miR-25 may be a promising therapeutic approach to treat patients with cisplatin-resistant GC.

Antibiotic anisomycin induces cell cycle arrest and apoptosis through inhibiting mitochondrial biogenesis in osteosarcoma.

The anti-cancer activities of antibiotic anisomycin have been demonstrated in kidney, colon and ovarian cancers whereas its underlying mechanisms are not well elucidated. In this work, we investigated whether anisomycin is effective in sensitizes osteosarcoma cell response to chemotherapy. We show that anisomycin inhibits proliferation via inducing osteosarcoma cell arrest at G2/M phase, accompanied by the increased levels of mitotic marker cyclin B and the decreased levels of Rb and E2F-1. Anisomycin also induces apoptosis in a caspase-dependent manner in osteosarcoma cells. Importantly, anisomycin is less effective in normal control NIH3T3 cells compared to osteosarcoma cells. In addition, anisomycin inhibits osteosarcoma growth in xenograft mouse model and enhances the inhibitory effects of doxorubicin in osteosarcoma in vitro and in vivo. Mechanistically, anisomycin targets mitochondrial biogenesis in osteosarcoma as shown by the decreased mitochondrial membrane potential, suppressed mitochondrial respiration via decreasing complex I activity, reduced ATP production. Furthermore, mitochondrial biogenesis stimulator acetyl-L-Carnitine (ALCAR) significantly rescues the inhibitory effects of anisomycin in osteosarcoma cells. Our work demonstrates that anisomycin is active against osteosarcoma cells and the molecular mechanism of its action is the inhibition of mitochondrial biogenesis.

Diverse functions of miR-373 in cancer.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression post-transcriptionally. They are involved in almost all cellular processes, and many have been described as potential oncogenes or tumor suppressors. MicroRNA-373 (miR-373), which was first identified as a human embryonic stem cell (ESC)-specific miRNA, is suggested to be implicated in the regulation of cell proliferation, apoptosis, senescence, migration and invasion, as well as DNA damage repair following hypoxia stress. Deregulation of miR-373 has been demonstrated in a number of cancers, whether it acts as an oncogene or a tumor suppressor, however, seems to be context dependent. In this review, we focus on the diverse functions of miR-373 and its implication in cancers.