title: Geranylgeranylacetone blocks doxorubicin-induced cardiac toxicity and reduces cancer cell growth and invasion through RHO pathway inhibition.
abstract: Doxorubicin is a widely used chemotherapy for solid tumors and hematologic malignancies, but its use is limited due to cardiotoxicity. Geranylgeranylacetone (GGA), an antiulcer agent used in Japan for 30 years, has no significant adverse effects, and unexpectedly reduces ovarian cancer progression in mice. Because GGA reduces oxidative stress in brain and heart, we hypothesized that GGA would prevent oxidative stress of doxorubicin cardiac toxicity and improve doxorubicin's chemotherapeutic effects. Nude mice implanted with MDA-MB-231 breast cancer cells were studied after chronic treatment with doxorubicin, doxorubicin/GGA, GGA, or saline. Transthoracic echocardiography was used to monitor systolic heart function and xenografts evaluated. Mice were euthanized and cardiac tissue evaluated for reactive oxygen species generation, TUNEL assay, and RHO/ROCK pathway analysis. Tumor metastases were evaluated in lung sections. In vitro studies using Boyden chambers were performed to evaluate GGA effects on RHO pathway activator lysophosphatidic acid (LPA)-induced motility and invasion. We found that GGA reduced doxorubicin cardiac toxicity, preserved cardiac function, prevented TUNEL-positive cardiac cell death, and reduced doxorubicin-induced oxidant production in a nitric oxide synthase-dependent and independent manner. GGA also reduced heart doxorubicin-induced ROCK1 cleavage. Remarkably, in xenograft-implanted mice, combined GGA/doxorubicin treatment decreased tumor growth more effectively than doxorubicin treatment alone. As evidence of antitumor effect, GGA inhibited LPA-induced motility and invasion by MDA-MB-231 cells. These anti-invasive effects of GGA were suppressed by geranylgeraniol suggesting GGA inhibits RHO pathway through blocking geranylation. Thus, GGA protects the heart from doxorubicin chemotherapy-induced injury and improves anticancer efficacy of doxorubicin in breast cancer.
authors.affiliation: Authors' Affiliations: Departments of Molecular and Comparative Pathobiology, and.
authors.forename: Polina
authors.initials: P
authors.lastname: Sysa-Shah
authors.affiliation: Authors' Affiliations: Departments of Molecular and Comparative Pathobiology, and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Authors' Affiliations: Departments of Molecular and Comparative Pathobiology, and.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Authors' Affiliations: Departments of Molecular and Comparative Pathobiology, and.
authors.forename: Scott
authors.initials: S
authors.lastname: Pin
authors.affiliation: Authors' Affiliations: Departments of Molecular and Comparative Pathobiology, and.
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.affiliation: Authors' Affiliations: Departments of Molecular and Comparative Pathobiology, and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bartock
authors.affiliation: Authors' Affiliations: Departments of Molecular and Comparative Pathobiology, and.
authors.forename: Allison
authors.initials: A
authors.lastname: Tsao
authors.affiliation: Authors' Affiliations: Departments of Molecular and Comparative Pathobiology, and.
authors.forename: Angela
authors.initials: A
authors.lastname: Hsieh
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
authors.affiliation: Cardiology, Johns Hopkins Medical Institutions;
authors.forename: An
authors.initials: A
authors.lastname: Moens
authors.affiliation: Department of Radiology, Johns Hopkins University;
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Hajime
authors.initials: H
authors.lastname: Orita
authors.affiliation: Authors' Affiliations: Departments of Molecular and Comparative Pathobiology, and kgabriel@jhmi.edu.
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000009:adverse effects / Q000494:pharmacology*; D004317:Doxorubicin / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D004317:Doxorubicin; D054460:rho-Associated Kinases; C031049:geranylgeranylacetone