Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks.
OBJECTIVE
As chemotherapy and molecular therapy improve the systemic survival of breast cancer patients, the incidence of brain metastases increases. Few therapeutic strategies exist for the treatment of brain metastases because the blood-brain barrier severely limits drug access. We report the pharmacokinetic, efficacy, and mechanism of action studies for the histone deactylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in a preclinical model of brain metastasis of triple-negative breast cancer.


METHODS
The 231-BR brain trophic subline of the MDA-MB-231 human breast cancer cell line was injected into immunocompromised mice for pharmacokinetic and metastasis studies. Pharmacodynamic studies compared histone acetylation, apoptosis, proliferation, and DNA damage in vitro and in vivo.


RESULTS
Following systemic administration, uptake of [(14)C]vorinostat was significant into normal rodent brain and accumulation was up to 3-fold higher in a proportion of metastases formed by 231-BR cells. Vorinostat prevented the development of 231-BR micrometastases by 28% (P = 0.017) and large metastases by 62% (P < 0.0001) compared with vehicle-treated mice when treatment was initiated on day 3 post-injection. The inhibitory activity of vorinostat as a single agent was linked to a novel function in vivo: induction of DNA double-strand breaks associated with the down-regulation of the DNA repair gene Rad52.


CONCLUSIONS
We report the first preclinical data for the prevention of brain metastasis of triple-negative breast cancer. Vorinostat is brain permeable and can prevent the formation of brain metastases by 62%. Its mechanism of action involves the induction of DNA double-strand breaks, suggesting rational combinations with DNA active drugs or radiation.
Women's Cancers Section, Laboratory of Molecular Pharmacology, Genetics Branch, National Cancer Institute/NIH, Bethesda, Maryland, USA. palmierd@mail.nih.gov
Diane
D
Palmieri
Paul R
PR
Lockman
Fancy C
FC
Thomas
Emily
E
Hua
Jeanne
J
Herring
Elizabeth
E
Hargrave
Matthew
M
Johnson
Natasha
N
Flores
Yongzhen
Y
Qian
Eleazar
E
Vega-Valle
Kunal S
KS
Taskar
Vinay
V
Rudraraju
Rajendar K
RK
Mittapalli
Julie A
JA
Gaasch
Kaci A
KA
Bohn
Helen R
HR
Thorsheim
David J
DJ
Liewehr
Sean
S
Davis
John F
JF
Reilly
Robert
R
Walker
Julie L
JL
Bronder
Lionel
L
Feigenbaum
Seth M
SM
Steinberg
Kevin
K
Camphausen
Paul S
PS
Meltzer
Victoria M
VM
Richon
Quentin R
QR
Smith
Patricia S
PS
Steeg
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000517:prevention & control* / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006655:Histone Deacetylases; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D006655:Histone Deacetylases