title: Knockdown of ROS1 gene sensitizes breast tumor growth to doxorubicin in a syngeneic mouse model.
abstract: Treatment of breast cancer, the second leading cause of female deaths worldwide, with classical drugs is often accompanied by treatment failure and relapse of disease condition. Development of chemoresistance and drug toxicity compels compromising the drug concentration below the threshold level with the consequence of therapeutic inefficacy. Moreover, amplification and over-activation of proto-oncogenes in tumor cells make the treatment more challenging. The oncogene, ROS1 which is highly expressed in diverse types of cancers including breast carcinoma, functions as a survival protein aiding cancer progression. Thus we speculated that selective silencing of ROS1 gene by carrier-mediated delivery of siRNA might sensitize the cancer cells to the classical drugs at a relatively low concentration. In this investigation we showed that intracellular delivery of c-ROS1-targeting siRNA using pH-sensitive inorganic nanoparticles of carbonate apatite sensitizes mouse breast cancer cells (4T1) to doxorubicin, but not to cisplatin or paclitaxel, with the highest enhancement in chemosensitivity obtained at 40 nM of the drug concentration. Although intravenous administrations of ROS1-loaded nanoparticles reduced growth of the tumor, a further substantial effect on growth retardation was noted when the mice were treated with the siRNA- and Dox-bound particles, thus suggesting that silencing of ROS1 gene could sensitize the mouse breast cancer cells both in vitro and in vivo to doxorubicin as a result of synergistic effect of the gene knockdown and the drug action, eventually preventing activation of the survival pathway protein, AKT1. Our findings therefore provide valuable insight into the potential cross-talk between the pathways of ROS1 and doxorubicin for future development of effective therapeutics for breast cancer.
authors.affiliation: Advanced Engineering Platform (AEP) and Jeffrey Cheah School of Medicine and Health Sciences, Monash University (Sunway campus), Petaling Jaya, Selangor 46150, Malaysia.
authors.forename: Snigdha
authors.initials: S
authors.lastname: Tiash
authors.affiliation: Advanced Engineering Platform (AEP) and Jeffrey Cheah School of Medicine and Health Sciences, Monash University (Sunway campus), Petaling Jaya, Selangor 46150, Malaysia.
authors.forename: Ming Jang
authors.initials: MJ
authors.lastname: Chua
authors.affiliation: Advanced Engineering Platform (AEP) and Jeffrey Cheah School of Medicine and Health Sciences, Monash University (Sunway campus), Petaling Jaya, Selangor 46150, Malaysia.
authors.forename: Ezharul Hoque
authors.initials: EH
authors.lastname: Chowdhury
mesh_terms: D000818:Animals; D001031:Apatites / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D055785:Gene Knockdown Techniques; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D011897:Random Allocation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D001031:Apatites; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C030782:carboapatite; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; C483813:Ros1 protein, mouse; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel; D002945:Cisplatin