TY - JOUR
T1 - Histone deacetylase inhibitor 2-hexyl-4-pentynoic acid enhances hydroxyurea therapeutic effect in triple-negative breast cancer cells
AU - Ding, Chenxia
AU - Su, Benyu
AU - Li, Qiaoling
AU - Ding, Wenwen
AU - Liu, Guochao
AU - Cai, Zuchao
AU - Zhang, Fengmei
AU - Lim, David
AU - Feng, Zhihui
PY - 2022
Y1 - 2022
N2 - Triple-negative breast cancer (TNBC) treatment has only limited effect, and it causes a significant number of deaths. Histone deacetylase inhibitors (HDACis) are emerging as promising anti-tumor agents in many types of cancers. We thus hypothesized that 2-hexyl-4-pentynoic acid (HPTA), a novel HDACi, could sensitize TNBC to hydroxyurea (HU, a ribonucleotide reductase inhibitor). In the present study, we investigated the effect of HPTA, alone or in combination with HU on cell survival, DNA double-strand breaks (DSBs), key homologous recombination (HR) repair proteins and cell cycle progression in MDA-MB-468 and MDA-MB-231 human TNBC cell lines. HPTA and HU synergistically inhibited the survival of TNBC cell lines and resulted in the accumulation of DNA double-strand breaks (DSBs). HPTA can sensitize TNBC cells to HU by inhibiting replication protein A2 (RPA2) hyperphosphorylation-mediated HR repair, and lessen cell accumulation in S-phase by inhibiting ATR-CHK1 signaling pathway. Taken together, our data suggested that HPTA enhances HU therapeutic effect by blocking the HR repair and regulating cell cycle progression in TNBC.
AB - Triple-negative breast cancer (TNBC) treatment has only limited effect, and it causes a significant number of deaths. Histone deacetylase inhibitors (HDACis) are emerging as promising anti-tumor agents in many types of cancers. We thus hypothesized that 2-hexyl-4-pentynoic acid (HPTA), a novel HDACi, could sensitize TNBC to hydroxyurea (HU, a ribonucleotide reductase inhibitor). In the present study, we investigated the effect of HPTA, alone or in combination with HU on cell survival, DNA double-strand breaks (DSBs), key homologous recombination (HR) repair proteins and cell cycle progression in MDA-MB-468 and MDA-MB-231 human TNBC cell lines. HPTA and HU synergistically inhibited the survival of TNBC cell lines and resulted in the accumulation of DNA double-strand breaks (DSBs). HPTA can sensitize TNBC cells to HU by inhibiting replication protein A2 (RPA2) hyperphosphorylation-mediated HR repair, and lessen cell accumulation in S-phase by inhibiting ATR-CHK1 signaling pathway. Taken together, our data suggested that HPTA enhances HU therapeutic effect by blocking the HR repair and regulating cell cycle progression in TNBC.
UR - https://hdl.handle.net/1959.7/uws:61952
U2 - 10.1016/j.mrgentox.2021.503422
DO - 10.1016/j.mrgentox.2021.503422
M3 - Article
SN - 1383-5718
VL - 873
JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
M1 - 503422
ER -
