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- W1219869037 abstract "Doxorubicin (DOX) is a risk factor for lymphedema in breast cancer patients after surgery and/or radiation. The mechanisms by which DOX contributes to lymphedema are unclear. We hypothesized that DOX directly inhibits lymph vessel (LV) spontaneous contractions and lymph flow by opening ryanodine receptors (RyRs). Calcium (Ca) released by RyRs is known to inactivate voltage-gated L-type Ca channels which are required for LV contractions. Isolated rat mesenteric LVs were cannulated, pressurized (4-5 mm Hg) and equilibrated in physiological salt solution (37°C) until contractions were stable. Edge-detection software recorded changes in external diameter. Adding DOX (0.5 to 20 µmol/L) to the bath solution progressively diminished LV contractions, culminating in reductions in amplitude (~70%), area under the curve (~62%), resting diameter (~24%), and frequency (~30%) (n=12). Incubation with dantrolene (10 µmol/L), a clinically available RyR1 inhibitor, alone had no effect on LV contractions but significantly attenuated DOX-induced suppression of contractile activity (n=6). High-resolution, intravital optical imaging of rat mesenteric LVs in vivo revealed that topically applied DOX (1 µmol/L) reduced lymph flow such that 70% of active LVs showed slow or no flow (t=20 mins, n=10). Thus, DOX may contribute to lymphedema by opening RyR1s to suppress LV contractions and flow, and clinically available dantrolene may be an unrecognized therapeutic option. Funded by Rho Chi-AFPE Graduate Fellowship (AJS), a UAMS Pilot Grant (NJ, EG), and NIH/NCI R01CA131164 (VZ)." @default.
- W1219869037 created "2016-06-24" @default.
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- W1219869037 date "2015-04-01" @default.
- W1219869037 modified "2023-09-26" @default.
- W1219869037 title "Doxorubicin Inhibition of Lymphatic Function is Mediated by Ryanodine Receptors and Prevented by Dantrolene" @default.
- W1219869037 doi "https://doi.org/10.1096/fasebj.29.1_supplement.785.12" @default.
- W1219869037 hasPublicationYear "2015" @default.
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