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Molecular Targeting of RRM2, NF-κB, and Mutant TP53 for the Treatment of Triple-Negative Breast Cancer.
Wilson, Elizabeth A; Sultana, Nahid; Shah, Khyati N; Elford, Howard L; Faridi, Jesika S.
Afiliação
  • Wilson EA; Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, California.
  • Sultana N; Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, California.
  • Shah KN; Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, California.
  • Elford HL; Molecules for Health, Inc., Richmond, Virginia.
  • Faridi JS; Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, California. jfaridi@pacific.edu.
Mol Cancer Ther ; 20(4): 655-664, 2021 04.
Article em En | MEDLINE | ID: mdl-33536192
Doxorubicin and other anthracycline derivatives are frequently used as part of the adjuvant chemotherapy regimen for triple-negative breast cancer (TNBC). Although effective, doxorubicin is known for its off-target and toxic side effect profile, particularly with respect to the myocardium, often resulting in left ventricular (LV) dysfunction and congestive heart failure when used at cumulative doses exceeding 400 mg/m2 Previously, we have observed that the ribonucleotide reductase subunit M2 (RRM2) is significantly overexpressed in estrogen receptor (ER)-negative cells as compared with ER-positive breast cancer cells. Here, we inhibited RRM2 in ER-negative breast cancer cells as a target for therapy in this difficult-to-treat population. We observed that through the use of didox, a ribonucleotide reductase inhibitor, the reduction in RRM2 was accompanied by reduced NF-κB activity in vitro When didox was used in combination with doxorubicin, we observed significant downregulation of NF-κB proteins accompanied by reduced TNBC cell proliferation. As well, we observed that protein levels of mutant p53 were significantly reduced by didox or combination therapy in vitro Xenograft studies showed that combination therapy was found to be synergistic in vivo, resulting in a significantly reduced tumor volume as compared with doxorubicin monotherapy. In addition, the use of didox was also found to ameliorate the toxic myocardial effects of doxorubicin in vivo as measured by heart mass, LV diameter, and serum troponin T levels. The data present a novel and promising approach for the treatment of TNBC that merits further clinical evaluation in humans.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ribonucleosídeo Difosfato Redutase / NF-kappa B / Proteína Supressora de Tumor p53 / Terapia de Alvo Molecular / Neoplasias de Mama Triplo Negativas Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ribonucleosídeo Difosfato Redutase / NF-kappa B / Proteína Supressora de Tumor p53 / Terapia de Alvo Molecular / Neoplasias de Mama Triplo Negativas Idioma: En Ano de publicação: 2021 Tipo de documento: Article