Ketorolac salt is a newly discovered DDX3 inhibitor to treat oral cancer.
DDX3 belongs to DEAD box RNA helicase family and is involved in the progression of several types of cancer. In this work, we employed a High Throughput Virtual screening approach to identify bioactive compounds against DDX3 from ZINC natural database. Ketorolac salt was selected based on its binding free energy less than or equals to -5 Kcal/mol with reference to existing synthetic DDX3 inhibitors and strong hydrogen bond interactions as similar to crystallized DDX3 protein (2I4I). The anti-cancer activity of Ketorolac salt against DDX3 was tested using oral squamous cell carcinoma (OSCC) cell lines. This compound significantly down regulated the expression of DDX3 in human OSCC line (H357) and the half maximal growth inhibitory concentration (IC50) of Ketorolac salt in H357 cell line is 2.6 µM. Ketorolac salt also inhibited the ATP hydrolysis by directly interacting with DDX3. More importantly, we observed decreased number of neoplastic tongue lesions and reduced lesion severity in Ketorolac salt treated groups in a carcinogen induced tongue tumor mouse model. Taken together, our result demonstrates that Ketorolac salt is a newly discovered bioactive compound against DDX3 and this compound can be used as an ideal drug candidate to treat DDX3 associated oral cancer.
1] Institute of Life Sciences, Bhubaneswar-751023, Odisha, India [2] Manipal University, Manipal-576104, Karnataka, India.
Sabindra K
SK
Samal
Department of Oral Pathology &Microbiology, Institute of Dental Sciences, 'Siksha O Anusandhan' University, Bhubaneswar-751003, Odisha, India.
Samapika
S
Routray
Biomedical Research Laboratory, Department of Biotechnology, KLEF University (Koneru Lakshmaiah Education Foundation) Vaddeswaram, Guntur, Andhra Pradesh, India.
Ganesh Kumar
GK
Veeramachaneni
Institute of Life Sciences, Bhubaneswar-751023, Odisha, India.
Rupesh
R
Dash
1] Biomedical Research Laboratory, Department of Biotechnology, KLEF University (Koneru Lakshmaiah Education Foundation) Vaddeswaram, Guntur, Andhra Pradesh, India [2] Sweety Biologicals India Private Limited, VengalRao Nagar, Kavali-524201, Andhra Pradesh, India.
Mahendran
M
Botlagunta
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D020910:Ketorolac / Q000008:administration & dosage*; D007928:Lethal Dose 50; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy / Q000379:methods; D012492:Salts / Q000008:administration & dosage; D014062:Tongue Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D012492:Salts; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases; D020910:Ketorolac