Abstract
Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, and combining a HDACi with other agents is an attractive therapeutic strategy in solid tumors. We report here that mevastatin increases HDACi LBH589-induced cell death in triple-negative breast cancer (TNBC) cells. Combination treatment inhibited autophagic flux by preventing Vps34/Beclin 1 complex formation and downregulating prenylated Rab7, an active form of the small GTPase necessary for autophagosome-lysosome fusion. This means that co-treatment with mevastatin and LBH589 activated LKB1/AMPK signaling and subsequently inhibited mTOR. Co-treatment also led to cell cycle arrest in G2/M phase and induced corresponding expression changes of proteins regulating the cell cycle. Co-treatment also increased apoptosis both in vitro and in vivo, and reduced tumor volumes in xenografted mice. Our results indicate that disruption of autophagosome-lysosome fusion likely underlies mevastatin-LBH589 synergistic anticancer effects. This study confirms the synergistic efficacy of, and demonstrates a potential therapeutic role for mevastatin plus LBH589 in targeting aggressive TNBC, and presents a novel therapeutic strategy for further clinical study. Further screening for novel autophagy modulators could be an efficient approach to enhance HDACi-induced cell death in solid tumors.
Highlights
Breast cancer is the second leading cause of cancerrelated deaths among women in the United States, with over 246,660 new diagnoses expected in 2016 and approximately 40,450 deaths [1]
Histone deacetylase inhibitors (HDACi) are effective as single agents against a subset of hematological tumors, they are less effective in solid tumors [7]
We show that the combination of mevastatin [18] and LBH589 inhibits triple-negative breast cancer (TNBC) cell proliferation by downregulating the cell cycle regulator, cyclin D1, upregulating P21 activity, and enhancing apoptosis
Summary
Breast cancer is the second leading cause of cancerrelated deaths among women in the United States, with over 246,660 new diagnoses expected in 2016 and approximately 40,450 deaths [1]. Current clinical therapies include hormone-based agents that directly target estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) [2, 3]. Triplenegative breast cancer (TNBC) is ER-, PR- and HER2negative, and accounts for approximately 15% of all breast cancers [3,4,5]. HDACi are effective as single agents against a subset of hematological tumors, they are less effective in solid tumors [7]. HDACi have shown promising synergistic or additive antitumor effects in combination with other antitumor agents [9, 12,13,14]
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