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.
|Luo, Yi; Shao, Lijian; Chang, Jianhui et al. (2018) M1 and M2 macrophages differentially regulate hematopoietic stem cell self-renewal and ex vivo expansion. Blood Adv 2:859-870|
|Alexander, Tyler C; Simecka, Christy M; Kiffer, Frederico et al. (2018) Changes in cognition and dendritic complexity following intrathecal methotrexate and cytarabine treatment in a juvenile murine model. Behav Brain Res 346:21-28|
|Liu, Xingui; Wang, Yingying; Zhang, Xuan et al. (2018) Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation. Bioorg Med Chem 26:3925-3938|
|Nukala, Ujwani; Thakkar, Shraddha; Krager, Kimberly J et al. (2018) Antioxidant Tocols as Radiation Countermeasures (Challenges to be Addressed to Use Tocols as Radiation Countermeasures in Humans). Antioxidants (Basel) 7:|
|Yadlapalli, Jai Shankar K; Dogra, Navdeep; Walbaum, Anqi W et al. (2018) Pinprick hypo- and hyperalgesia in diabetic rats: Can diet content affect experimental outcome? Neurosci Lett 673:24-27|
|Nekouei, Mina; Ghezellou, Parviz; Aliahmadi, Atousa et al. (2018) Changes in biophysical characteristics of PFN1 due to mutation causing amyotrophic lateral sclerosis. Metab Brain Dis 33:1975-1984|
|Cheema, Amrita K; Byrum, Stephanie D; Sharma, Neel Kamal et al. (2018) Proteomic Changes in Mouse Spleen after Radiation-Induced Injury and its Modulation by Gamma-Tocotrienol. Radiat Res 190:449-463|
|Skinner, Charles M; Miousse, Isabelle R; Ewing, Laura E et al. (2018) Impact of obesity on the toxicity of a multi-ingredient dietary supplement, OxyELITE Pro™ (New Formula), using the novel NZO/HILtJ obese mouse model: Physiological and mechanistic assessments. Food Chem Toxicol 122:21-32|
|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|
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