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Activation of the Anaphase Promoting Complex Reverses Multiple Drug Resistant Cancer in a Canine Model of Multiple
Terra G Arnason1,2,3, Valerie MacDonald-Dickinson4, Matthew Casey Gaunt4
1Division of Endocrinology and Metabolism, Department of Medicine, Saskatoon, SK S7N 0W8, Canada.
Abstract:
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.
Insights
Metformin treatment reduced multiple drug resistance (MDR) protein markers in canines with lymphoma. Activating the Anaphase Promoting Complex (APC) restored drug sensitivity in MDR cells, improving survival.
Area of Science:
- Veterinary Oncology
- Cancer Biology
- Pharmacology
Background:
- Canine lymphoma shares chemotherapy resistance mechanisms with human cancers, making dogs valuable models for studying drug resistance.
- Insulin-sensitizers, like metformin, have shown promise in reducing cancer incidence and reversing drug resistance in vitro.
- Multiple drug resistance (MDR) is a significant challenge in treating canine lymphoma.
Purpose of the Study:
- To evaluate metformin's clinical efficacy in canines with MDR lymphoma.
- To investigate metformin's impact on MDR biomarkers and gene expression in canine lymphoma.
- To explore the role of the Anaphase Promoting Complex (APC) in MDR and metformin's therapeutic effects.
Main Methods:
- Canines with MDR lymphoma were treated with metformin.
- Tumor biopsies and mRNA microarrays were used to assess changes in MDR biomarkers and gene expression.
- In vitro studies with canine lymphoma cells validated the role of APC activation in restoring chemosensitivity.
Main Results:
- Metformin reduced MDR protein markers in all treated canines.
- A 290-gene set enriched in Anaphase Promoting Complex (APC) substrates was identified in MDR tumors, indicating slowed mitotic progression.
- APC activation was associated with remission and restored chemosensitivity in MDR cells.
- MDR cells exhibited reduced APC activity.
Conclusions:
- Metformin shows potential for treating MDR canine lymphoma.
- Targeting the Anaphase Promoting Complex (APC) by promoting its activation may overcome MDR in lymphoma.
- Activating the APC in drug-resistant cells may improve mitotic progression, leading to enhanced survival and disease-free duration.
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