Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies.
Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies.
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DOI：
10.1371/journal.pone.0090675
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Furukawa Y
中科院分区：
文献类型：
--
作者：
Hiraoka N;Kikuchi J;Yamauchi T;Koyama D;Wada T;Uesawa M;Akutsu M;Mori S;Nakamura Y;Ueda T;Kano Y;Furukawa Y
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Bendamustine has shown considerable clinical activity against indolent lymphoid malignancies as a single agent or in combination with rituximab, but combination with additional anti-cancer drugs may be required for refractory and/or relapsed cases as well as other intractable tumors. In this study, we attempted to determine suitable anti-cancer drugs to be combined with bendamustine for the treatment of mantle cell lymphoma, diffuse large B-cell lymphoma, aggressive lymphomas and multiple myeloma, all of which are relatively resistant to this drug, and investigated the mechanisms underlying synergism. Isobologram analysis revealed that bendamustine had synergistic effects with alkylating agents (4-hydroperoxy-cyclophosphamide, chlorambucil and melphalan) and pyrimidine analogues (cytosine arabinoside, gemcitabine and decitabine) in HBL-2, B104, Namalwa and U266 cell lines, which represent the above entities respectively. In cell cycle analysis, bendamustine induced late S-phase arrest, which was enhanced by 4-hydroperoxy-cyclophosphamide, and potentiated early S-phase arrest by cytosine arabinoside (Ara-C), followed by a robust increase in the size of sub-G1 fractions. Bendamustine was able to elicit DNA damage response and subsequent apoptosis faster and with shorter exposure than other alkylating agents due to rapid intracellular incorporation via equilibrative nucleoside transporters (ENTs). Furthermore, bendamustine increased the expression of ENT1 at both mRNA and protein levels and enhanced the uptake of Ara-C and subsequent increase in Ara-C triphosphate (Ara-CTP) in HBL-2 cells to an extent comparable with the purine analog fludarabine. These purine analog-like properties of bendamustine may underlie favorable combinations with other alkylators and pyrimidine analogues. Our findings may provide a theoretical basis for the development of more effective bendamustine-based combination therapies.
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苯达莫司汀和恩替司他的组合通过诱导细胞凋亡和 DNA 损伤反应协同抑制多发性骨髓瘤细胞的增殖。
影响因子：
9.7
作者：
Cai, Bo;Lyu, Hui;Huang, Jingcao;Wang, Shuiliang;Lee, Choon-Kee;Gao, Chunji;Liu, Bolin
通讯作者：
Liu, Bolin
影响因子：
20.3
作者：
Gandhi, V;Estey, E;Plunkett, W
通讯作者：
Plunkett, W
影响因子：
3.5
作者：
Hitz, F.;Fischer, N.;Mey, U.
通讯作者：
Mey, U.
影响因子：
3.7
作者：
Beeharry N;Rattner JB;Bellacosa A;Smith MR;Yen TJ
通讯作者：
Yen TJ
影响因子：
11.5
作者：
Leoni, Lorenzo M.;Bailey, Brandi;Niemeyer, Christina C.
通讯作者：
Niemeyer, Christina C.