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Abstract

Abstract: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). Background:RNA helicases mainly found in all eukaryotes and most prokaryotes. These were distinguished from others based on highly conserved four amino-acid residues (Asp (D)-Glu (E)-Ala (A)-Asp/His (D/H)) at N-terminal region and helicase domain at C-terminal end [1,2]. This amino acid motif has been found in more than 500 proteins and has shown to represent up to 2% of the open reading frames of a genome and may share overlapping or distinct biological cellular functions [3]. These proteins have shown to associate with several aspects of energydependent RNA metabolism including translation, ribosome biogenesis, and pre-mRNA splicing [4, 5]. Unlike DEAH box genes, DEAD box genes have been identified on all human chromosomes except 15, 18, and 21. This highlights the importance that DEAD box RNA helicases in the physiological management of the cell and its survival. Among several DEAD box RNA helicases, DDX3 is located on X-chromosome at Xp11.3-p11.23 [6]. It has a functional homologue on the Y chromosome, DBY, and this gene product has an activity that is crucial for normal spermatogenesis [7-9]. It has shown to participate in human folliculogenesis and its deletion has shown to represent an important genetic cause of primary amenorrhea or impairment of female fertility [10].