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.

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.

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.

Platelet factor 4 inhibits IL-17/Stat3 pathway via upregulation of SOCS3 expression in melanoma.

Platelet factor 4 (PF4) was the first discovered CXC chemokine and is found in platelet granules at very high concentration. Now, it is becoming increasingly evident that PF4 actively participates in inflammation and immune response. Recent paper demonstrated that PF4 limits the development and response of the Th17 cells and assisted in regulatory T cell development in transplantation. But, the immunoregulatory role of PF4 in tumor has little known and needs to be further investigated. In our current study, wild-type mice are inoculated with melanoma cell line B16-F10 (1 × 10(6)/mouse) and treated with PF4. PF4 inhibits B16 tumor growth and decreases γδ cell infiltration. The expression of interleukin (IL)-17, IL-6, and p-signal transducer and activator of transcription-3 (Stat3) was markedly decreased with treatment of PF4 compared with control in vivo and in vitro. And, the suppressed tumor growth induced by PF4 is abolished by additional treatment of recombinant mouse IL (rmIL)-17. PF4 also induces suppressor of cytokine signaling 3 (SOCS3) upregulations, and PF4 fails to suppress expression of p-Stat3, IL-17, and IL-6 in cells transfected with SOCS3 short interfering RNA (siRNA). In conclusion, PF4 inhibits IL-17/Stat3 pathway via upregulation of SOCS3 expression and may contribute to suppressing tumor growth in murine models of melanoma.