Botlagunta Mahendran, Kollapalli Bhulakshmi, Kakarla Lavanya, Gajarla Siva Priya, Gade Sai Pujitha, Dadi Chandra Lekha, Penumadu Akhila, Javeed Shaik
Department of Biotechnology, K L University, Guntur, Andhra Pradesh-522502, India; Sweety Biologicals India Private Limited,Kavali, Andhra Pradesh-524201, India.
Department of Biotechnology, K L University, Guntur, Andhra Pradesh-522502, India.
Bioinformation. 2016 Oct 18;12(7):347-353. doi: 10.6026/97320630012347. eCollection 2016.
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).
RNA解旋酶DDX3是一种多功能酶，已知与多种疾病相关，如HIV进展、脑癌和乳腺癌。一些环扩展核苷化合物，如REN: NZ51、稠合二咪唑二氮杂卓环（RK33）、（Z）-3-（5-（3-溴亚苄基）-4-氧代-2-硫代噻唑烷-3-基）-N-（2-羟基苯基）丙酰胺化合物（FE15）已被证明可抑制DDX3解旋酶活性。然而，这些药物的合成仅限于少数研究小组。通过文献研究发现，使用计算机模拟分子对接方法，阿霉素与结晶形式的DDX3形成强氢键相互作用。为了评估阿霉素的生物抑制作用，我们使用H357癌细胞系进行了ATP酶活性测定和抗癌活性实验。结果表明，阿霉素通过直接与DDX3相互作用，持续降低无机磷酸盐（Pi）的释放并抑制ATP水解。通过MTT法检测抗癌活性。阿霉素对H357癌细胞系的半数最大抑制浓度（IC50）为50μM，并且阿霉素还显著下调了DDX3的表达。综上所述，我们的结果表明，通过与独特氨基酸残基（苏氨酸198）和常见氨基酸残基（酪氨酸200和苏氨酸201）相互作用，使用阿霉素抑制DDX3表达可作为治疗DDX3相关癌症疾病的理想候选药物。
