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Vorinostat (SAHA) and Breast Cancer: An Overview.

ABSTRACT: Vorinostat (SAHA), an inhibitor of class I and II of histone deacetylases, is the first histone deacetylase inhibitor (HDI) approved for the treatment of cutaneous T-cell lymphoma in 2006. HDIs are promising anticancer agents that inhibit the proliferation of many types of cancer cells including breast carcinoma (BC). BC is a heterogeneous disease with variable biological behavior, morphological features, and response to therapy. Although significant progress in the treatment of BC has been made, high toxicity to normal cells, serious side effects, and the occurrence of multi-drug resistance limit the effective therapy of BC patients. Therefore, new active agents which improve the effectiveness of currently used regimens are highly needed. This manuscript analyzes preclinical and clinical trials data of SAHA, applied individually or in combination with other anticancer agents, considering different histological subtypes of BC.

SUBMITTER: Wawruszak A

PROVIDER: S-EPMC8468501 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Vorinostat (SAHA) and Breast Cancer: An Overview.

Wawruszak Anna A Borkiewicz Lidia L Okon Estera E Kukula-Koch Wirginia W Afshan Syeda S Halasa Marta M

Cancers 20210919 18

Vorinostat (SAHA), an inhibitor of class I and II of histone deacetylases, is the first histone deacetylase inhibitor (HDI) approved for the treatment of cutaneous T-cell lymphoma in 2006. HDIs are promising anticancer agents that inhibit the proliferation of many types of cancer cells including breast carcinoma (BC). BC is a heterogeneous disease with variable biological behavior, morphological features, and response to therapy. Although significant progress in the treatment of BC has been made ...[more]

PMID: 34572928

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Project description:Histone deacetylase (Hdac) inhibitors are used clinically to treat cancer and epilepsy. Although Hdac inhibition accelerates osteoblast maturation and suppresses osteoclast maturation in vitro, the effects of Hdac inhibitors on the skeleton are not understood. The purpose of this study was to determine how the pan-Hdac inhibitor, suberoylanilide hydroxamic acid (SAHA; a.k.a. vorinostat or Zolinza(TM)) affects bone mass and remodeling in vivo. Male C57BL/6J mice received daily SAHA (100mg/kg) or vehicle injections for 3 to 4weeks. SAHA decreased trabecular bone volume fraction and trabecular number in the distal femur. Cortical bone at the femoral midshaft was not affected. SAHA reduced serum levels of P1NP, a bone formation marker, and also suppressed tibial mRNA levels of type I collagen, osteocalcin and osteopontin, but did not alter Runx2 or osterix transcripts. SAHA decreased histological measures of osteoblast number but interestingly increased indices of osteoblast activity including mineral apposition rate and bone formation rate. Neither serum (TRAcP 5b) nor histological markers of bone resorption were affected by SAHA. P1NP levels returned to baseline in animals which were allowed to recover for 4weeks after 4weeks of daily SAHA injections, but bone density remained low. In vitro, SAHA suppressed osteogenic colony formation, decreased osteoblastic gene expression, induced cell cycle arrest, and caused DNA damage in bone marrow-derived adherent cells. Collectively, these data demonstrate that bone loss following treatment with SAHA is primarily due to a reduction in osteoblast number. Moreover, these decreases in osteoblast number can be attributed to the deleterious effects of SAHA on immature osteoblasts, even while mature osteoblasts are resistant to the harmful effects and demonstrate increased activity in vivo, indicating that the response of osteoblasts to SAHA is dependent upon their differentiation state. These studies suggest that clinical use of SAHA and other Hdac inhibitors to treat cancer, epilepsy or other conditions may potentially compromise skeletal structure and function.

Dataset Information

Vorinostat (SAHA) and Breast Cancer: An Overview.

Publications

Vorinostat (SAHA) and Breast Cancer: An Overview.

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