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Combined treatment of canine osteosarcoma cells with gene knock-down and chemotherapy

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Title: Combined treatment of canine osteosarcoma cells with gene knock-down and chemotherapy
Author: Gallienne, Jacqueline
Department: Department of Pathobiology
Program: Pathobiology
Advisor: Wood, Geoffrey
Abstract: Companion animals, such as the dog, can spontaneously develop cancers just like humans. Canine osteosarcoma (OSA) is a highly aggressive type of bone cancer that shares striking disease similarities with human OSA, including molecular aberrations to the R1 alpha regulatory subunit of cyclic AMP-dependent protein kinase A, or PRKAR1A. Low PRKAR1A-expressing tumours are associated with the best post-chemotherapy response in human OSA patients, and similarly, canine patients with low PRKAR1a protein expression in their primary tumours lived significantly longer post-chemotherapy treatment compared to dogs with high PRKAR1a-expressing tumours. Knowing this, we sought to investigate the in vitro effects of gene knock-down in canine OSA cells using small interfering RNAs (siRNAs) directed against PRKAR1A mRNA transcripts. Here, we hypothesized that PRKAR1a knock-down would enhance sensitivity to conventional chemotherapeutic drugs, including doxorubicin and carboplatin. The present study included four canine OSA cell lines, one commercially available D17 cell line and three primary cell lines, each with different endogenous PRKAR1a protein expression levels. Our findings show that PRKAR1a knock-down as a treatment alone reduced cellular viability and increased apoptosis in some canine OSA cell lines, although no gross changes were detected in soft agar growth. Interestingly, pretreatment with PRKAR1A siRNAs enhanced chemosensitivity to doxorubicin in some canine OSA cell lines; however no significant benefit was detected if PRKAR1A silencing was combined with carboplatin chemotherapy. Overall, this study prompts further investigation into PRKAR1a as a potential therapeutic target to sensitize bone cancer cells to chemotherapy, leading to enhanced treatment efficacy and improved patient survival for both humans and dogs.
URI: http://hdl.handle.net/10214/8351
Date: 2014-08


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