In vitro anti-cancer activity of doxorubicin against human RNA helicase, DDX3.
In vitro anti-cancer activity of doxorubicin against human RNA helicase, DDX3.
复制标题
DOI：
10.6026/97320630012347
复制
发表时间：
2016
期刊：
影响因子：
1.9
通讯作者：
Javeed S
中科院分区：
文献类型：
--
作者：
Botlagunta M;Kollapalli B;Kakarla L;Gajarla SP;Gade SP;Dadi CL;Penumadu A;Javeed S
RNA解旋酶，DDX3是一种多功能酶，已知与多种疾病有关，如艾滋病毒进展，脑和乳腺癌。一些扩环的核苷化合物，如Ren：NZ51，稠合双咪唑二氮杂环(RK33)，(Z)-3-(5-(3-溴benzylidene)-4-oxo-2-thioxothiazolidin-3-yl)-N-(2-羟基苯基)丙酰胺化合物(FE15))可以抑制DDX3解旋酶的活性。然而，这些药物的合成仅限于少数几个研究小组。广泛的文献研究发现，阿霉素与结晶型的DDX3通过分子对接方式形成了较强的氢键相互作用。为了评价阿霉素的生物抑制作用，我们用H357癌细胞株进行了ATPase活性测定和抗癌活性测定。结果表明，阿霉素通过直接与DDX3相互作用，持续抑制无机磷(PI)释放，抑制ATP水解酶活性。用四甲基偶氮唑盐比色法检测其抗癌活性。阿霉素对H357癌细胞的半数抑制浓度(IC50)为50μM，并可显著下调DDX3的表达。综上所述，我们的结果表明，通过与独特的氨基酸残基(Thr 198)和共同的氨基酸残基(Tyr 200和Thr 201)相互作用，阿霉素抑制DDX3的表达可以作为治疗DDX3相关癌症疾病的理想候选药物。
RNA helicase, DDX3 is a multifunctional enzyme and is known to be associated with several diseases like HIV progression, brain and breast cancer. Some of the ring expanded nucleoside compounds such as REN: NZ51, fused di imidazodiazepine ring (RK33), (Z)-3-(5- (3-bromo benzylidene)-4-oxo-2-thioxothiazolidin-3-yl)-N-(2- hydroxy phenyl) propanamide compound (FE15) have been documented to inhibit DDX3 helicase activity. However, synthesis of these drugs is limited to few research groups. Prevalence of literature study, we found that doxorubicin form strong hydrogen bond interactions with crystallized form of DDX3 using in-silico molecular docking approach. To evaluate the biological inhibitory action of doxorubicin, we performed the ATPase activity assay and anti-cancer activity using H357 cancer cell lines. Results showed that doxorubicin continually declined the inorganic phosphate (Pi) release and inhibited the ATP hydrolysis by directly interacting with DDX3. Anticancer activity was detected by MTT assay. The half maximal inhibitory concentrations of doxorubicin (IC50) for H357 cancer cell line is 50 μM and also doxorubicin significantly down regulated the expression of DDX3. Taken together, our results demonstrate, that inhibition of DDX3 expression by using doxorubicin can be used as an ideal drug candidate to treat DDX3 associated cancer disorder by interacting with unique amino acid residues (Thr 198) and common amino acid residues (Tyr 200 and Thr 201).