Раковая наука и терапия

Background: It is well known that Newcastle Disease Virus (NDV) AF2240 has antitumor activity against breast cancer cell lines. Several studies have thought this activity depend on direct viral oncolysis, which may not be the only factor that play a role in the antitumor effect of the virus. However, the mechanism underlying its antitumor effect is largely unresolved. In line with this observation, we postulated that NDV AF2240 may induce an in vitro production of Nitric Oxide (NO) and Tumor Necrosis Factor (TNF-α) in RAW 264.7 macrophages for cytotoxic activity on breast cancer cells.

Methods: NDV AF2240 were subjected to different experimental conditions (Live, UV-inactivated and Heatinactivated), different Heamagglutination (HA) titer of the virus were co-cultured with RAW 264.7 cells to get the cell-free supernatant. Levels of TNF-α, and NO production were measured by ELISA and Griess assay respectively. MTT assay was later used to determine their cytotoxicity on MDA-MB-231 breast cancer cell line in vitro.

Results: NDV was found to be an excellent inducer in RAW 264.7 macrophage cells of TNF-α (P<0.05) and NO production (P<0.05) when compared with the negative control. The supernatant containing NO and TNF-α was also found to be cytotoxic against MDA-MB-231 cells (P<0.05) when compared with the negative control, indicating that viral replication was not necessary for their production, because UV-inactivated NDV for 15 minutes was almost as good as lived NDV. However, heat inactivated NDV did not induce TNF-α and NO production.

Conclusion: This suggests the relevance of TNF-α and NO in the indirect antitumor effect of NDV AF2240, and also shown that mare contact between the macrophages and the NDV is enough to induce TNF-α and NO production in macrophages.

???????????: ???? ??????????????? 2 (COX-2) ???????? ? ???????????? ????????? ?????? ??????????????? ???????????????, ??????? ??? ??????. ???? ???????, ??? ??????????, ??????????? ????????? COX-2, ?????????? ????????????-?????????????? ??????? (EMT) ? ??????????????? ???????????????? ????????. ????????, ??????????? ???????? ?????????? ????? ???????? ?????????? ???????, ????? ?? EMT ????? ?????? ?????? ?????????? ????, ????? ?????????. ???? ????????, ??? IL-27 ???????? ????????????????? ???????????, ? ???? ???????? ???????????? ????????, ??? IL-27 ?????????? EMT ????? ???????????? ???? STAT1.

????: ????? ??????? ???????????? ???????? ???????? ???? ??????????? ? ????????? ? ??-27 ? ????????????? ????????????? ?????? ????? ????????? ??? ??????????? ???????????? STAT.

?????? ? ??????????: ?????? ???????-????????? ???????, ??? ?????????? IL-27 ????????? ????? ????????????????? ???? ?????? ???????? (????) ???????? ? ????????? STAT1 ? STAT3, ???????? ????? Snail ? ?????????????? ???????? (N-????????? ? ?????????) ? ?????????????? ?????????? ?????????? ????????????? ???????? (E-?????????, β- ? γ-?????????), ? ????? ????????????? ???????? ??????. ????????? ??????????? ? IL-27 ??????? ? ???????? ????????? STAT1. ?????? ?????????????? IL-27 ????????? STAT3 ???? ??????? ??? ?????????? ???????????. STAT1 siRNA ?????????????? ??? ??????????? ??????? ???? STAT1 ? ????????? ????????????? ??? ? ???????? ?????? ??? ??????????????? ??????? IL-27 ? ????????????. ??????????????? ????????? ?????? siRNA STAT1 ???????? ?????? ???????????????? IL-27 ? ??????????? ? ????????? STAT1 ? STAT3. ????? ????, ?????????? ?????????? ????????????? ????????, ????????? ?????????? ?????????????? ???????? ? ??????????? ???????? ?????? ??????????????? ?????????? ????? ???? ????????? siRNA STAT1, ??? ????????? ????????????, ??? ???? STAT1 ????? ??? ???????? ??????? ??????????????? ?????????.

??????????: ??????????????? ?????????? ??????????? ? ??-27 ????????? ????????? ???????? ?? ????????????? ????????????-??????????????? ???????? ? ????????? ???????? ? ??????? ???? ?????? ???????? ????? ???????????? ???? STAT1.

??? ???????? ???????????? ????? ???????? ????????? ??? ???????????????? ??????????????? ???????????????. ?????????????? ??????? ???????????? ????? ???????, ??? ?????????? ??? ?????????, ?????????????? ?????????? ????? ???????????? ???????????. ?? ??????????? ?????? ???????? ???????????? ??????, ????? ????????, ??? ??????????, ????? ???? ???????? ?????????????? ?? ???????????????? ???????????. ????? ?????????, ?????????? ???????????? ????? ????????????? ??????? ??? ????, ? ??? ???????????? ????????, ??? ?? ???????? ?? ??????????????? ??????? ? ???????????????? ??? ??????????? ????? ????, ??????? ??? ????????. ??????? ???????? ? ??????????? ????? ??????????? ??????? ? ???????????? ?????????? ???? ???????. ? ????????? ???? ??????????? ????????? ???????????? ???????? ? ????? ????????? ????? ????? ??? ?????????? ??????????? ????????????????? ??????? ???????. ????? ?????? ???????? ??????? ???? ???????? ??????? ?????, ??????? ?????? ?????? ???? ? ?????????? ????????? ??????????? ?, ????? ???????, ??????????? ????? ??????????? ???????, ??????? ?????? ???????? ???? ? ????????? ???? ???????????????? ???????????? ??????????, ??? ????? ??????????? ??? ??????????????? ? ????????????????. ????? ???????? ???????? ?????? ????? ????????? ??????? (VEGF), ?????? ????? ??????????? (PDGF), ?????? ????? ???????????? (FGF) ? ???????? ?????????? ???????????? (Ang)/Tie 2. ??? ????? ?????? ???????? ???? ? ???????????? ?????, ????????????? ?????? ?????????? ??????, ? ? ????????? ????? ??? ???????????? ???????????? ????????????, ???????? ? ?????? ???????? ?????????? ??????????????? ???????, ??????? ????? ??????????? ??? ??????????????? ??????????????? ???????? (???????????) ??? ? ????????? ? ???????? ???????? ???????, ?????? ??? ??????????? ????????????. ? ????? ????????? ????????? ???????????, ?????????, ??????? ?????????, ?????????, ??????????, ???????????, ?????????, ????????? ? ?????????. ????? ??????? ??????????? ?????? ?? ????????? ??????????? ??????, ??????? ??????????? ????? ????????? ???? ? ???????????, ???? ? ????????? ? ??????? ????????. ???? ???? ???????, ??????? ???? ??????????? ??? ?????? ? ????????????, ??????? ? ???? ??????.

????????? ???????????? ?????????? ?? ????? ?????? ????????? ????? ????????? ? ??????? ?????????? ????????????? ????? ???? ?????. ? ?????????????? ????? ???????????? ?????????? ????????????? ????? FGFR2 ? TGFB1 ? ????????? ???? ????? ???? ??????? ? ????????? ?????????, ??? ????? ??????? ??? ??????????? ?????? ??????? ? ????????????? ???????????????? ??? ?????????????? ????????? ??????????? ? ??????? ???????. ??????????? ???????? ??, ??? ?? ???????????????? 100 ????????, ??????? ?????????, ??????????? ??? ???????????, ? ??????????, ??? ?????? ????????? TC FGFR2 rs1219648 ? rs2981582 ???? ????? ??????? ? ?????? ???? ?????, ????? ??? ?????? ????????? TC TGFB1 rs1800470 ???? ?????????? ? ????????? ???????, ???? ? ?? ? ???? ?????????, ??? ???????????? ?? ????? ? ???????? ???????????? ????? ???? ? ???????, ????????????? ? ?????? ???????? ? ?????, ? ??? ????? ????????? ?????? ????? ? ?????? ???? ?????. ? ???? ??????????? ?????????? ?? ????????????????, ??? ??????? ? ??????????? T ? ????????? ????????? 88 ?? ??????? ???????????????? ?????? ?? ????????????, ?. ?. ??????????????????, ????? ??? ? ??? ? ??????????? C ???????????? ???? ???????????. ?????? in silico ???????, ??? ??????? FGFR2 ????????? ? ????????? ???????. ????? ?? ?????????????? ??? ????????? ???????. ????? ?? ?????????????? ??? ????????? ???????, ? ????????? ????????? ??????? TGFB1 ? ???????? ???????? ?????? ????????? ? ??? ????????? ?? ????????? -??????, ??????? ????????? ??????????? ???????. ????????? ??????? ????????? ???????, ??? ? ????? ????????? ??? ???????? ?????? ????? ?????? ? ?????? ????????? ?????, ??? ?????????????, ???????? ???????????? ??? ? ?????????????? ??????? ? ????? ????? ? ?????????? ??????? ???????? ??????. ?????????????? ?????? ???????, ??? ??????? ???? ???????? ?????? ? ???????? ?????? 40 ??? ????. ????? ???? ????????, ??? ???????, ? ??????? ???? ???? ????? 30 ???, ???? ????? ???????????? ? ???? ???????? ??????. ???????? P ???? ?????? 0,1, ??? ?? ???????? ????????, ????????? ??? ??????? ?????????????????? ? ????? ????????, ??????????? ???????? ?????????. ???????????????? ?????? ????? ??? ???????? ?? ????? ?????. ? FGFR2 ???? ? ??????? ????????? ? ????? ? ??? ?? ?????????, ????????? ?????? ?????, ????? ??? ? TGFB1 ?????? ? ???????? ?????????? ???????????? ? ?????????. ???? ?????? ??????? ? ?????? ???????????? ????????? ??? ???????????????, ????? ????????? ??????? ?? ?????????.

?????????????????????? ??????????????? ????????? ?????? ? ??? (????) ???????? ??????? ???????????? ??-?? ?????????? ??????????? ??????? ??????? ???? ? ????? ???????????? ???????? (?????????? ???????????? ?? ????????? 40%). ??? ????????? ? ??????????????? ? ?????????????? ???? ??????????? ???????? ???????? ?????????? ???????????/??????? ? ???????????, ?? ??????? ????? ???????????? ??? ???? ?????? ????????? ???????? ???? 11%. ????????? ????????? ???? ?????????????? ??????????? ???????? ????????????? ????????????? ????????????, ???????? ????????????????? ???????? ?????, ????????????-?????????????? ??????? ? ???????? ???????.

?????????? ?????? ???????? ???? ? ???????? ? ???????????? HNSCC. ????????? ????? ?????? ?? ??????????? ??????? ??????????? ????????? ??????????, ? ???? ?????? ????????? ??? ?????????????? ??????????????? ??????? ? ????????????? ??? ??????????? ???????????????? ???????????. ?????????????? ????????????? ?????????? ? ???????????? ??????????? ???????? ??? ?????????, ?? ?? ??? ??? ??? ????????????? ?????? ? ???????? ??????????????? ??????? ??? HNC.

????? ?????? ?????? ???????? ???????????? ???? ??????????? ??????????? ??? ???? ?????? ? ???.

???????????: ?????? ?????????????? ?????? ??????? ??????? ??????, ??????? ????????? ??????????? ? ???, ?? ??????????? ?????? ? ?????????????? ??? ??????? ??????????????? ????????????? ?????????????? ???????. RuvB-???????? (RUVBL) 2 ???????? ?????? ??????? ???????? ??????????, ????? ??? TIP60 ? INO80, ??????? ????????? ? ??????????????? ????????? ? ??????? ?? ??????????? ??? ? ?? ??????????????. ???????????? ???? ???????????? ??????? ???? RUVBL2 ? ????????? ?????? ????? ??????????? ?????????????? ???????.

??????: ?? ???????? RUVBL2 ? ???????????? ??????? MRC5-SV ? ??????? ????? ??????????????? (si) ??? ? ??????? ???????????????? ?????? ? ???????????????????? ?????????????? ???????, ??????? ????????? (cisPt), 2'-???????-5-?????????? (azadC) ? ????????? C (MMC), ? ????? ? ?????????? ???????, ???????????? ???, ??????? ????????????? ????.

??????????: ????????????? ???????? ? 10 ?? siRUVBL2 ????????? 80% ?? 3-? ???? ????? ???????????, ? ??????? (>65%) ?????????? ?? 6-? ????. ???? ?????? ??????????? ?????????? ??-?? ????????? RUVBL2 ?? ????????? ? ????????, ????????????? ?????? ? ??????????? siRNA, ??? ????????? ?? ??, ??? RUVBL2 ????????? ??? ???????????? ??????. ?????? ? ?????????? RUVBL2 ???? ???????? ????????????? ? cisPt, azadC ? ????????????? ?????. ?????????? ???????????????? ? MMC ???? ??????????????.

??????????: ????????? RUVBL2 ? ??????? ??????? ????????? ???????????????? ? ?????????????? ??????? ? ????????????? ?????, ????????????????, ?? ???? ?????????? ????????? ???????????? ???????????????? ????????? ????????????? ????????? ?????????????? ???????? ???, ???????????? ??????????????? ??? ???????? ??????????????? ???????? ??? ?????????????? ??????. ?????????? ?????????? ???????????? ??? ????????? ?????? ???? RUVBL2 ? ???? ????????.

Purpose: A major impediment to successful drug therapy is the development of multidrug resistance (MDR). Drug resistance in HIV patients is also well known. The introduction of highly active antiretroviral therapy (HAART) has substantially reduced HIV resistance and fatalities. It appears that ritonavir along with another protease inhibitor regulates both drug efflux and metabolism to overcome resistance. Therefore, we have examined a similar strategy of combining ritonavir with anticancer drugs to modulate drug efflux, metabolism and allow sufficient drug entry into tumor cells.

Methods: Cells were treated for 72 hours with anticancer drugs alone and in the presence of ritonavir. Quantitative gene expression studies, immunoblot analysis, radioactive uptake studies and Vivid™ fluorescent assay were performed on human colon adenocarcinoma cells (LS180) cells. Cell proliferation, migration and apoptosis assays were performed on human breast adenocarcinoma (T47D) cells and prostate cancer (PC-3) cells.

Results: The overexpression of efflux transporters and metabolizing enzymes was diminished when cells were co-treated with ritonavir. [3H] Lopinavir uptake and VIVID™ assay further confirmed the functional activity of transcribed genes upon co-treatment. When the anticancer agent (doxorubicin, paclitaxel, tamoxifen or vinblastine) was combined with ritonavir, a significantly diminished cell proliferation and migration and augmented caspase activity leading to apoptosis was observed in T47D and PC-3 cells.

Conclusions: Combination therapy of anticancer drug with ritonavir may overcome drug resistance by deactivating the overexpression of efflux transporters and metabolizing enzymes. Therefore, drug regimens containing ritonavir would enhance therapeutic exposure of cancer cells to anticancer agents, potentially improving chemotherapeutic efficacy and consequently devoid of resistance.