We will develop mitochondria-targeted antioxidants (MTAs) and imaging probes that will mitigate cardiotoxicity and enhance antitumor efficacies of chemotherapeutic drugs. We will use doxorubicin (DOX), a front-line antitumor agent in breast cancer treatment. DOX causes delayed dose-dependent cardiotoxicity. Clinically, this side effect is managed with conventional antioxidants and iron chelators. This proposal provides a new adjuvant approach in breast cancer chemotherapy. Its genesis is based upon the following discoveries: 1) MTAs (e.g., Mito-Q, a synthetic drug analog of an endogenous antioxidant, Co-enzyme-Q, present in the mitochondrial respiratory chain) inhibit DOX-mediated cardiotoxicity in a preclinical animal model and in cardiomyocytes, and 2) MTAs (Mito-Q and Mito-CP, a nitroxide targeted to mitochondria) cause antiproliferative and cytotoxic effects in breast cancer cells (MCF-7 and MDA-MB-231) but not in non- transformed breast epithelial cells (MCF-10A) and significantly enhance DOX-induced breast cancer cell toxicity. We hypothesize that mitochondria-targeted antioxidants enhance DOX-mediated antitumor effects but attenuate DOX cardiotoxicity. Response to chemotherapy will be monitored by using the mitochondria-targeted technetium-labeled imaging agents (99mTc-Mito10-MAG3) in a chemically-induced breast carcinoma animal model. Specifically, we will: (i) Investigate the cytotoxic effects of MTAs alone and with DOX in breast cancer cells, (ii) Assess the cytotoxic effects of MTAs and DOX in breast cancer cells overexpressing multi-drug resistant protein, (iii) Evaluate the adjuvant chemotherapeutic effects of MTAs and DOX in an in vivo breast cancer model, and (iv) Assess the cardioprotective and oxy-radical scavenging effects of MTAs in DOX- treated cardiomyocytes and in DOX-treated rat cardiomyopathy model.
These aims will be accomplished using HPLC-fluorescence and HPLC-electrochemical detection techniques, scintimammography and echocardiography. Abnormal generation of reactive oxygen species will be detected using novel species- and target-specific probes. We will develop innovative MTA-based adjuvant therapy that can be used to inhibit DOX-induced cardiotoxicity. This research may potentially lead to novel ways for improving the therapeutic efficacy of DOX and other antitumor agents used in breast cancer treatment.

Public Health Relevance

The proposed research is clinically relevant in that results obtained from this work will likely mitigate the adverse side effects associated with breast cancer chemotherapy. This work will also enable early detection of breast cancer in an animal model using a novel imaging technique.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA152810-03
Application #
8271285
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
2010-06-14
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$305,938
Indirect Cost
$104,663
Name
Medical College of Wisconsin
Department
Biophysics
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Zielonka, Jacek; Joseph, Joy; Sikora, Adam et al. (2017) Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications. Chem Rev 117:10043-10120
Kalyanaraman, Balaraman; Hardy, Micael; Podsiadly, Radoslaw et al. (2017) Recent developments in detection of superoxide radical anion and hydrogen peroxide: Opportunities, challenges, and implications in redox signaling. Arch Biochem Biophys 617:38-47
Cheng, Gang; Zielonka, Jacek; Ouari, Olivier et al. (2016) Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells. Cancer Res 76:3904-15
Cheng, Gang; Zielonka, Jacek; McAllister, Donna et al. (2015) Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bioenergetics and energy-sensing mechanism. Cancer Lett 365:96-106
Zhang, Qi; Pan, Jing; Lubet, Ronald A et al. (2015) Enhanced antitumor activity of 3-bromopyruvate in combination with rapamycin in vivo and in vitro. Cancer Prev Res (Phila) 8:318-26
Cheng, G; Zielonka, J; McAllister, D et al. (2014) Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation. Br J Cancer 111:85-93
Hardy, Micael; Poulhés, Florent; Rizzato, Egon et al. (2014) Mitochondria-targeted spin traps: synthesis, superoxide spin trapping, and mitochondrial uptake. Chem Res Toxicol 27:1155-65
Cheng, Gang; Zielonka, Jacek; McAllister, Donna M et al. (2013) Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death. BMC Cancer 13:285
Dickey, Jennifer S; Gonzalez, Yanira; Aryal, Baikuntha et al. (2013) Mito-tempol and dexrazoxane exhibit cardioprotective and chemotherapeutic effects through specific protein oxidation and autophagy in a syngeneic breast tumor preclinical model. PLoS One 8:e70575
Cunniff, Brian; Benson, Kira; Stumpff, Jason et al. (2013) Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells. J Cell Physiol 228:835-45

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