Like humans, canine
lymphomas are treated by
chemotherapy cocktails and frequently develop multiple drug resistance (MDR). Their shortened clinical timelines and
tumor accessibility make canines excellent models to study MDR mechanisms.
Insulin-sensitizers have been shown to reduce the incidence of
cancer in humans prescribed them, and we previously demonstrated that they also reverse and delay MDR development in vitro. Here, we treated canines with MDR
lymphoma with
metformin to assess clinical and tumoral responses, including changes in MDR
biomarkers, and used
mRNA microarrays to determine differential gene expression.
Metformin reduced MDR
protein markers in all canines in the study. Microarrays performed on mRNAs gathered through longitudinal
tumor sampling identified a 290 gene set that was enriched in
Anaphase Promoting Complex (APC) substrates and additional mRNAs associated with slowed mitotic progression in MDR samples compared to skin controls. mRNAs from a canine that went into remission showed that APC substrate mRNAs were decreased, indicating that the APC was activated during remission. In vitro validation using canine
lymphoma cells selected for resistance to chemotherapeutic drugs confirmed that APC activation restored MDR chemosensitivity, and that APC activity was reduced in MDR cells. This supports the idea that rapidly pushing MDR cells that harbor high loads of
chromosome instability through mitosis, by activating the APC, contributes to improved survival and disease-free duration.