Unlocking the chromatin of adenoid cystic carcinomas using HDAC inhibitors sensitize cancer stem cells to cisplatin and induces tumor senescence.
Unlocking the chromatin of adenoid cystic carcinomas using HDAC inhibitors sensitize cancer stem cells to cisplatin and induces tumor senescence.
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DOI：
10.1016/j.scr.2017.04.003
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发表时间：
2017-05
影响因子：
1.2
通讯作者：
Squarize CH
中科院分区：
文献类型：
--
作者：
Almeida LO;Guimarães DM;Martins MD;Martins MAT;Warner KA;Nör JE;Castilho RM;Squarize CH
腺样囊性癌是一种罕见的涎腺恶性肿瘤，其特点是局部复发和远处转移，由于其抵抗常规治疗。基于铂的疗法已被广泛探索作为ACC的治疗方法，但它们几乎没有效果。研究表明，一组具有癌症干细胞（CSC）特征的特定肿瘤细胞参与了骨髓性白血病、乳腺癌、结直肠癌和胰腺癌的化疗耐药性。靶向CSC的治疗策略通过降低肿瘤复发率来改善患者的存活率，并且表观遗传药物，如组蛋白脱乙酰酶抑制剂（HDACi），已经显示出靶向CSC的有希望的结果。在这项研究中，我们研究了HDACi Suberoylanilide异羟肟酸（伏立诺他）和顺铂单独或联合对ACC的CSC和非CSC的影响。我们使用CSC作为患者来源的异种移植物（PDX）样品和ACC原代细胞中肿瘤对治疗耐药的生物标志物。我们发现顺铂降低了肿瘤活力，但富集了CSC的群体。伏立诺他的全身给药减少了体内和体外可检测到的CSC的数量，并且低剂量的伏立诺他降低了肿瘤细胞活力。然而，伏立诺他和顺铂的组合通过激活细胞衰老在耗尽CSC和降低所有ACC原代细胞中的肿瘤活力方面极其有效。这些观察结果表明HDACi和嵌入剂组合更有效地破坏肿瘤细胞及其干细胞。
Adenoid cystic carcinoma (ACC) is an uncommon malignancy of the salivary glands that is characterized by local recurrence and distant metastasis due to its resistance to conventional therapy. Platinum-based therapies have been extensively explored as a treatment for ACC, but they show little effectiveness. Studies have shown that a specific group of tumor cells, harboring characteristics of cancer stem cells (CSCs), are involved in chemoresistance of myeloid leukemias, breast, colorectal and pancreatic carcinomas. Therapeutic strategies that target CSCs improve the survival of patients by decreasing the rates of tumor relapse, and epigenetic drugs, such as histone deacetylase inhibitors (HDACi), have shown promising results in targeting CSCs. In this study, we investigated the effect of the HDACi Suberoylanilide hydroxamic acid (Vorinostat), and cisplatin, alone or in combination, on CSCs and non-CSCs from ACC. We used CSCs as a biological marker for tumor resistance to therapy in patient-derived xenograft (PDX) samples and ACC primary cells. We found that cisplatin reduced tumor viability, but enriched the population of CSCs. Systemic administration of Vorinostat reduced the number of detectable CSCs in vivo and in vitro, and a low dose of Vorinostat decreased tumor cell viability. However, the combination of Vorinostat and cisplatin was extremely effective in depleting CSCs and reducing tumor viability in all ACC primary cells by activating cellular senescence. These observations suggest that HDACi and intercalating agents act more efficiently in combination to destroy tumor cells and their stem cells.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
21.3
作者：
Etchegaray JP;Chavez L;Huang Y;Ross KN;Choi J;Martinez-Pastor B;Walsh RM;Sommer CA;Lienhard M;Gladden A;Kugel S;Silberman DM;Ramaswamy S;Mostoslavsky G;Hochedlinger K;Goren A;Rao A;Mostoslavsky R
通讯作者：
Mostoslavsky R
影响因子：
9
作者：
Deruy E;Nassour J;Martin N;Vercamer C;Malaquin N;Bertout J;Chelli F;Pourtier A;Pluquet O;Abbadie C
通讯作者：
Abbadie C
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS