Lymphedema is a major complication after radiation and/or surgery for breast cancer. Unfortunately, there are no medications to effectively treat it. Serious complications include pain, lymphangitis, cellulitis, ulcers, and the development of malignant lymphangiosarcomas. Doxorubicin (DOX) is a central chemotherapeutic agent for treating breast cancer, but it increases the risk of lymphedema by 4- to 5-fold. The mechanism by which DOX contributes to the development of lymphedema is unknown, but it is thought to relate to its cytotoxic action. However, we propose that clinical concentrations of DOX directly inhibit the rhythmic contractions of lymph vessels (LVs) that propel lymph fluid from tissues back to the heart to prevent lymphedema. These contractions are tightly controlled by the calcium concentration and redox state in LVs. High-resolution in vivo imaging also reveals that systemically administered DOX profoundly reduces lymph flow. The suppression of LV contractile function by DOX is largely prevented by both dantrolene (DANT), a clinically available blocker of ryanodine receptors (RYRs), and MitoTEMPO, a mitochondrial-specific reactive oxygen species (mitoROS) scavenger. These data, along with knowledge that DOX activates RYRs and induces mitochondrial dysfunction in striated muscle and recent discoveries of functional RYRs in LVs, have led us to hypothesize that: DOX acutely opens RYRs to increase cytosolic calcium and mitoROS in lymph muscle cells (LMCs), resulting in the loss of LV contractions and inducing lymphostasis and lymphatic injury. Accordingly, we will explore whether DANT, an FDA-approved RYR blocker, can prevent DOX-induced lymphatic dysfunction.
Three aims will use an integration of techniques to explore this hypothesis and will rely on protein and functional analysis of isolated lymph muscle cells and whole LVs, use optical imaging to assess volumetric lymph flow in vivo in response to DOX and RYR blockade, and investigate the utility of DANT as a potential therapeutic in a rat breast tumor model.
Aim 1 will quantify the gene and protein expression profiles of RYR subtypes and determine whether DOX activates RYRs to increase cytosolic calcium and mitoROS generation as a mechanism of inhibiting LV contractions.
Aim 2 will evaluate if DANT represents a potential therapeutic option to prevent DOX- induced suppression of lymph flow and prevent DOX-induced lymphatic injury.
Aim 3 will investigate the effects of DANT on the anticancer activity of DOX in a rat model of breast cancer. Thus, we plan to explore RYRs as new therapeutic targets for DOX-related lymphedema and evaluate whether RYR blockers can be repurposed as anti-lymphedema medications.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arkansas for Medical Sciences
Little Rock
United States
Zip Code
Alam, Sinthia; Carter, Gwendolyn S; Krager, Kimberly J et al. (2018) PCB11 Metabolite, 3,3'-Dichlorobiphenyl-4-ol, Exposure Alters the Expression of Genes Governing Fatty Acid Metabolism in the Absence of Functional Sirtuin 3: Examining the Contribution of MnSOD. Antioxidants (Basel) 7:
Barham, Caroline; Fil, Daniel; Byrum, Stephanie D et al. (2018) RNA-Seq Analysis of Spinal Cord Tissues from hPFN1G118V Transgenic Mouse Model of ALS at Pre-symptomatic and End-Stages of Disease. Sci Rep 8:13737
Janganati, Venumadhav; Ponder, Jessica; Balasubramaniam, Meenakshisundaram et al. (2018) MMB triazole analogs are potent NF-?B inhibitors and anti-cancer agents against both hematological and solid tumor cells. Eur J Med Chem 157:562-581
Banerjee, Sudip; Shah, Sumit K; Melnyk, Stepan B et al. (2018) Cebpd Is Essential for Gamma-Tocotrienol Mediated Protection against Radiation-Induced Hematopoietic and Intestinal Injury. Antioxidants (Basel) 7:
Wang, Lei; Fang, Bin; Fujiwara, Toshifumi et al. (2018) Deletion of ferroportin in murine myeloid cells increases iron accumulation and stimulates osteoclastogenesis in vitro and in vivo. J Biol Chem 293:9248-9264
Harrill, Alison H; Lin, Haixia; Tobacyk, Julia et al. (2018) Mouse population-based evaluation of urinary protein and miRNA biomarker performance associated with cisplatin renal injury. Exp Biol Med (Maywood) 243:237-247
Zhang, Xin; Zhang, Suping; Liu, Xingui et al. (2018) Oxidation resistance 1 is a novel senolytic target. Aging Cell :e12780
Alexander, Tyler C; Butcher, Hannah; Krager, Kimberly et al. (2018) Behavioral Effects of Focal Irradiation in a Juvenile Murine Model. Radiat Res 189:605-617
He, Liu-Jun; Yang, Dong-Lin; Li, Shi-Qiang et al. (2018) Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells. Bioorg Med Chem 26:3899-3908
Kiaei, Mahmoud; Balasubramaniam, Meenakshisundaram; Govind Kumar, Vivek et al. (2018) ALS-causing mutations in profilin-1 alter its conformational dynamics: A computational approach to explain propensity for aggregation. Sci Rep 8:13102

Showing the most recent 10 out of 81 publications