TMC120 displayed potent cytotoxic effect on human cervical carcinoma through enhancing the polymerization of microtubules.

OBJECTIVE: In the post-HAART era, the incidence of some AIDS-defining cancers declined markedly likely reflecting HAART-related improvements in immunity, whereas incidence of some cancers such as cervical cancer has not been affected. Therefore, it is valuable to find whether antiretroviral drugs or prophylactic microbicides could treat or prevent these cancers, especially the cervical cancer. DESIGN: We screened the anti-HIV drugs, approved or in phase III clinical trials, to identify a potential anticancer drug candidate. METHODS: We chose cervical HeLa and SiHa cancer cells and focused on studying the antitumor effects in vitro and in vivo. Cell proliferation was measured by MTT assay, the cytotoxic effect was obtained through apoptosis as evidenced by Annexin V flow cytometry assay because of the arresting of cancer cells in G2/M phase of cell cycle. Nude mice xenograft model was performed to detect the antitumor effect in vivo. RESULTS: TMC120 was identified as a potential anticancer drug candidate. TMC120 displayed potent cytotoxic effect on various human cancer cells, including cervical carcinoma cell line HeLa and SiHa. Further mechanism study showed that TMC120 enhanced the polymerization of microtubules, which was followed by mitotic arrest, as well as abnormal mitotic spindles. TMC120 also substantially retarded the growth rate of the tumor in vivo. CONCLUSION: TMC120 is a potential chemoprophylactic and therapeutic agent for cervical cancers in a manner similar to paclitaxel, and could be suitable for helping healthy women to prevent HIV infection and cervical cancer.

A novel synthetic dibenzocyclooctadiene lignan analog XLYF-104-6 attenuates lipopolysaccharide-induced inflammatory response in RAW264.7 macrophage cells and protects BALB/c mice from sepsis.

The wide range of inflammation mechanisms under control by NF-κB makes this pathway as an attractive target for new anti-inflammatory drugs. Herein, we showed that a new dibenzocyclooctadiene lignan analog XLYF-104-6, with a chemical name of 1,2,3,10,11-pentamethoxydibenzocycloocta-6,7-[c] pyrrole-1,3-dione, inhibited lipopolysaccharide (LPS)-induced NF-κB activation in RAW264.7 cells through preventing IκBα degradation and p65 nuclear translocation. The inhibitory activity of this compound on NF-κB activation contributes to the reduction of LPS-induced TNF-α and IL-6 productions. Notably, XLYF-104-6 suppressed LPS-induced iNOS expression and NO production in a NF-κB independent manner, since IKK inhibitor BAY 11-7082 has failed to exert similar inhibitory effect on iNOS expression and NO production. In addition, XLFY-104-6 also exerted anti-inflammatory action in endotoxemic mice by decreasing plasma LPS-induced TNF-α and IL-1ß levels as well as increasing plasma LPS-induced IL-10 concentrations. These findings suggest XLYF-104-6 could act as a leading compound for developing a potential anti-inflammatory drug.

Sinomenine suppresses osteoclast formation and Mycobacterium tuberculosis H37Ra-induced bone loss by modulating RANKL signaling pathways.

Receptor activator of NF-κB ligand (RANKL) is essential for osteoclastogenesis. Targeting RANKL signaling pathways has been an encouraging strategy for treating lytic bone diseases such as osteoporosis and rheumatoid arthritis (RA). Sinomenine (SIN), derived from Chinese medicinal plant Sinomenioumacutum, is an active compound to treat RA, but its effect on osteoclasts has been hitherto unknown. In the present study, SIN was found to ameliorate M. tuberculosis H37Ra (Mt)-induced bone loss in rats with a decreased serum level of TRACP5b and RANKL, and an increased level of osteoprotegerin (OPG). In vitro study also showed that SIN could inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, MMP-9, TRACP were inhibited by SIN in a dose dependent manner. Signal transduction studies showed that SIN could obviously reduce the expression of RANK adaptor molecule TRAF6 and down-regulate RANKL-induced NF-κB activation. It decreased the RANKL-induced p38, JNK posphorylation but not ERK1/2 posphorylation. SIN could also reduce RANKL-mediated calcium influx which is associated with TRAF6/c-Src complex. Finally, SIN suppressed RANKL induced AP-1 and NFAT transcription, as well as the gene expression of NFATc1 and AP-1 components (Fra-1, Fra-2, c-Fos). The protein expression of c-Fos and TRAF6 were also inhibited by SIN after RANKL stimulation. Taken together, SIN could attenuate osteoclast formation and Mt-induced bone loss by mediating RANKL signaling pathways.