Discovery of drug transporter inhibitors tied to long noncoding RNA in resistant cancer cells; a computational model -in Silico-Study

Mohanad Diab ¹ Amel Hamdi ^2* Feras Al-Obeidat ³ Wael Hafez ^4,5* Ivan Cherrez-Ojeda ⁶ Muneir Gador ⁵ Gowhar Rashid ⁷ Sana F Elkhazin ¹ Samar Sami Alkafaas ⁸

• ¹ mediclinic airport road Hospital, Abu dhabi, United Arab Emirates
• ² Abu Dhabi University, Abu Dhabi, United Arab Emirates
• ³ Zayed University, Abu Dhabi, United Arab Emirates
• ⁴ Department of Internal Medicine, National Research Centre (Egypt), Cairo, Egypt
• ⁵ NMC Royal Hospital, Abu Dhabi, United Arab Emirates
• ⁶ Espiritu Santo University, Guayaquil, Guayas, Ecuador
• ⁷ Amity Institute of Applied Science, Amity University, Noida, Uttar Pradesh, India
• ⁸ Division of Biochemistry, Department of Chemistry, Faculty of Science, Tanta University, Tanta, Gharbia, Egypt

Chemotherapeutic resistance is a major obstacle to chemotherapeutic failure. Cancer cell resistance involves several mechanisms, including epithelial-to-mesenchymal transition (EMT), signaling pathway bypass, drug efflux activation, and impairment of drug entry. P-glycoproteins (P-gp) are an efflux transporter that pumps chemotherapeutic drugs out of cancer cells, resulting in chemotherapeutic resistance. Several types of long noncoding RNA (lncRNAs) have been identified in resistant cancer cells, including ODRUL, MALAT1, and ANRIL. The high expression level of ODRUL is related to the induction of ATP-binding cassette (ABC) gene expression, resulting in the emergence of doxorubicin resistance in osteosarcoma. lncRNAs are observed to be regulators of drug transporters in cancer cells such as MALAT1 and ANRIL. Targeting P-gp expression using natural products is a new strategy to overcome cancer cell resistance and improve the sensitivity of resistant cells toward chemotherapies. This review validates the inhibitory effects of natural products on P-gp expression and activity using in silico molecular docking. In silico analysis showed that Delphinidin and Asparagoside-f are the most significant natural product inhibitors of p-glycoprotein-1. These inhibitors can reverse multi-drug resistance and induce the sensitivity of resistant cancer cells toward chemotherapy based on in silico molecular docking. It is important to validate that pre-elementary docking can be confirmed using in vitro and in vivo experimental data.