Cardioprotective Effect of Phase 3 Clinical Anticancer Agent, RRx-001, in Doxorubicin-Induced Acute Cardiotoxicity in Mice

被引:14
作者
Oronsky, Bryan [1 ]
Ao-Ieong, Eileen S. Y. [2 ]
Yalcin, Ozlem [2 ]
Carter, Corey A. [1 ]
Cabrales, Pedro [2 ]
机构
[1] EpicentRx Inc, 11099 North Torrey Pines Rd,Suite 160, La Jolla, CA 92037 USA
[2] Univ Calif San Diego, Dept Bioengn, 9500 Gilman Dr, La Jolla, CA 92093 USA
关键词
RRx-001; cardioprotection; anthracycline; doxorubicin; angiotensin receptor blocker; PARTIAL-RESPONSE; CANCER; MECHANISMS; PREVENTION; THERAPY;
D O I
10.1021/acs.molpharmaceut.9b00150
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Anthracycline chemotherapy (e.g., doxorubicin or DOX) is associated with a cumulative dose-dependent cardiac dysfunction that may lead to congestive heart failure, which limits both its use and usefulness in the clinic. The cardiotoxicity may manifest acutely and/or months or years after treatment with doxorubicin has ended. Experimental and human data have demonstrated that angiotensin-converting enzyme/angiotensin-receptor antagonists mediate a cardio-protective effect against anthracycline toxicity. In this study, with the angiotensin receptor blocker, candesartan, as a positive control, we evaluated whether pretreatment with the hypoxic nitric oxide generating anticancer agent, RRx-001, could reduce acute DOX-induced cardiotoxicity. of 24 BALB/c mice were randomized for prophylactic treatment with vehicle, RRx-001, candesartan, or no-intervention control. Within each of the three intervention arms, mice received treatment with DOX. Murine pressure-volume analysis was performed with microconductance catheters to characterize the degree of cardiovascular dysfunction within each group. The following hemodynamic parameters were monitored: left ventricular systolic pressure (LVSP), heart rate, and maximal rate of increase of left ventricular pressure (+/- dP/dt(max)). Five days after doxorubicin injection, untreated (with RRx-001) mice displayed significantly impaired systolic (LVSP, -27%; dP/dt(max), -25%; left ventricular developed pressure (LVDP), +33%; P < 0.05) and global (stroke volume (SV), -52%; ejection fraction (EF), -20%; stroke work (SW), -62.5%; heart rate (HR), -18%; cardiac output (CO), -57%; mean blood arterial pressure (MAP), -30%; systemic vascular resistance (SVR), +20%; P < 0.05) LV functions when compared with the untreated (with RRx-001) group. In contrast, RRx-001-treated mice showed improved variables of systolic (LVSP, +27%; dP/dt(max), +25%; LVDP, -33%; P < 0.05) and global (SV, +52%; EF, +20%; SW, +62.5%; HR, +18%; CO, +57%; MAP, +30%; SVR, -20%; P < 0.05) LV functions compared with untreated doxorubicin mice. Similar to the positive control, candesartan, the cardiotoxic effects of DOX in mice were partially attenuated by the prophylactic administration of RRx-001. These results suggest that RRx-001 as a multifunctional anticancer agent, which sensitizes cancer cells to the cytotoxic effects of chemotherapy and radiation, may also have beneficial cardioprotective effects.
引用
收藏
页码:2929 / 2934
页数:6
相关论文
共 30 条
  • [1] Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk
    Barrett-Lee, P. J.
    Dixon, J. M.
    Farrell, C.
    Jones, A.
    Leonard, R.
    Murray, N.
    Palmieri, C.
    Plummer, C. J.
    Stanley, A.
    Verrill, M. W.
    [J]. ANNALS OF ONCOLOGY, 2009, 20 (05) : 816 - 827
  • [2] The macrophage stimulating anti-cancer agent, RRx-001, protects against ischemia-reperfusion injury
    Cabrales, Pedro
    Caroen, Scott
    Oronsky, Arnold
    Carter, Corey
    Trepel, Jane
    Summers, Thomas
    Reid, Tony
    Oronsky, Neil
    Lybeck, Michelle
    Oronsky, Bryan
    [J]. EXPERT REVIEW OF HEMATOLOGY, 2017, 10 (06) : 575 - 582
  • [3] Caron H. N., 2002, COCHRANE DB SYST REV, V16
  • [4] RRx-001 in Refractory Small-Cell Lung Carcinoma: A Case Report of a Partial Response after a Third Reintroduction of Platinum Doublets
    Carter, Corey A.
    Oronsky, Bryan T.
    Caroen, Scott Z.
    Scicinski, Jan J.
    Degesys, Aiste
    Kim, Michelle M.
    Oronsky, Arnold L.
    Lybeck, Harry
    Cabrales, Pedro
    Oronsky, Neil
    Reid, Tony
    Roswarski, Joseph
    Brzezniak, Christina
    [J]. CASE REPORTS IN ONCOLOGY, 2016, 9 (01): : 171 - 176
  • [5] Partial Response to Platinum Doublets in Refractory EGFR-Positive Non-Small Cell Lung Cancer Patients after RRx-001: Evidence of Episensitization
    Carter, Corey A.
    Oronsky, Bryan T.
    Caroen, Scott Z.
    Scicinski, Jan J.
    Cabrales, Pedro
    Reid, Tony
    Degesys, Aiste
    Jenkins, John
    Brzezniak, Christina
    [J]. CASE REPORTS IN ONCOLOGY, 2016, 9 (01): : 62 - 67
  • [6] A Novel Angiotensin Type I Receptor Antagonist, Fimasartan, Prevents Doxorubicin-induced Cardiotoxicity in Rats
    Chang, Sung-A
    Lim, Byung-Kwan
    Lee, You Jung
    Hong, Mi-Kyung
    Choi, Jin-Oh
    Jeon, Eun-Seok
    [J]. JOURNAL OF KOREAN MEDICAL SCIENCE, 2015, 30 (05) : 559 - 568
  • [7] Late Mortality After Dexrazoxane Treatment: A Report From the Children's Oncology Group
    Chow, Eric J.
    Asselin, Barbara L.
    Schwartz, Cindy L.
    Doody, David R.
    Leisenring, Wendy M.
    Aggarwal, Sanjeev
    Baker, K. Scott
    Bhatia, Smita
    Constine, Louis S.
    Freyer, David R.
    Lipshultz, Steven E.
    Armenian, Saro H.
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (24) : 2639 - U90
  • [8] A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells
    Das, D. S.
    Ray, A.
    Das, A.
    Song, Y.
    Tian, Z.
    Oronsky, B.
    Richardson, P.
    Scicinski, J.
    Chauhan, D.
    Anderson, K. C.
    [J]. LEUKEMIA, 2016, 30 (11) : 2187 - 2197
  • [9] In vitro and in vivo study on the antioxidant activity of dexrazoxane
    Galetta, Fabio
    Franzoni, Ferdinando
    Cervetti, Giulia
    Regoli, Francesco
    Fallahi, Poupak
    Tocchini, Leonardo
    Carpi, Angelo
    Antonelli, Alessandro
    Petrini, Mario
    Santoro, Gino
    [J]. BIOMEDICINE & PHARMACOTHERAPY, 2010, 64 (04) : 259 - 263
  • [10] GIANNI L, 1985, J BIOL CHEM, V259, P6056