Doxorubicin in combination with a small TGFbeta inhibitor: a potential novel therapy for metastatic breast cancer in mouse models.
Doxorubicin in combination with a small TGFbeta inhibitor: a potential novel therapy for metastatic breast cancer in mouse models.
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DOI：
10.1371/journal.pone.0010365
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发表时间：
2010-04-28
期刊：
影响因子：
3.7
通讯作者：
Sun LZ
中科院分区：
文献类型：
--
作者：
Bandyopadhyay A;Wang L;Agyin J;Tang Y;Lin S;Yeh IT;De K;Sun LZ
最近的研究表明，诱导上皮间质转化（EMT）可能会赋予乳腺肿瘤细胞转移和自我更新的特性，导致耐药性和肿瘤复发。TGFβ是一种有效的EMT诱导剂，并已在各种乳腺癌细胞和动物模型中显示出促进肿瘤进展。我们报道化疗药物阿霉素激活人和鼠乳腺癌细胞中的TGFβ信号。阿霉素诱导小鼠乳腺癌4 T1细胞发生EMT，并促进其侵袭和干细胞表型细胞的生成，而TGFβ I型受体激酶抑制剂（TβRI-KI）可显著抑制阿霉素诱导的EMT。我们在转移性乳腺癌动物模型中研究了TβR1-KI联合阿霉素的潜在协同抗肿瘤活性。在4 T1原位异种移植模型中，与单药治疗相比，多柔比星和TβRI-KI联合治疗增强了多柔比星减少肿瘤生长和肺转移的疗效。阿霉素单独治疗可增强人乳腺癌MDA-MB-231原位异种移植模型中的肺转移和4 T1原位异种移植模型中的骨转移，当TβR1-KI与阿霉素联合给药时，可显著阻断骨转移。这些观察结果表明，肿瘤细胞中化疗药物对TGFβ通路的不利激活以及肿瘤微环境中TGFβ水平的升高可能导致EMT和癌症干细胞的产生，从而导致对化疗的抗性。我们的研究结果表明，多柔比星与TGFβ抑制剂的联合治疗有可能降低多柔比星的剂量，从而降低多柔比星的毒副作用，并提高其抑制乳腺癌生长和转移的疗效。
Recent studies suggested that induction of epithelial-mesenchymal transition (EMT) might confer both metastatic and self-renewal properties to breast tumor cells resulting in drug resistance and tumor recurrence. TGFβ is a potent inducer of EMT and has been shown to promote tumor progression in various breast cancer cell and animal models. We report that chemotherapeutic drug doxorubicin activates TGFβ signaling in human and murine breast cancer cells. Doxorubicin induced EMT, promoted invasion and enhanced generation of cells with stem cell phenotype in murine 4T1 breast cancer cells in vitro, which were significantly inhibited by a TGFβ type I receptor kinase inhibitor (TβRI-KI). We investigated the potential synergistic anti-tumor activity of TβR1-KI in combination with doxorubicin in animal models of metastatic breast cancer. Combination of Doxorubicin and TβRI-KI enhanced the efficacy of doxorubicin in reducing tumor growth and lung metastasis in the 4T1 orthotopic xenograft model in comparison to single treatments. Doxorubicin treatment alone enhanced metastasis to lung in the human breast cancer MDA-MB-231 orthotopic xenograft model and metastasis to bone in the 4T1 orthotopic xenograft model, which was significantly blocked when TβR1-KI was administered in combination with doxorubicin. These observations suggest that the adverse activation of TGFβ pathway by chemotherapeutics in the cancer cells together with elevated TGFβ levels in tumor microenvironment may lead to EMT and generation of cancer stem cells resulting in the resistance to the chemotherapy. Our results indicate that the combination treatment of doxorubicin with a TGFβ inhibitor has the potential to reduce the dose and consequently the toxic side-effects of doxorubicin, and improve its efficacy in the inhibition of breast cancer growth and metastasis.
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影响因子：
2.5
作者：
Dean, Michael
通讯作者：
Dean, Michael
影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
影响因子：
8.8
作者：
Gamucci T;D'Ottavio AM;Magnolfi E;Barduagni M;Vaccaro A;Sperduti I;Moscetti L;Belli F;Meliffi L
通讯作者：
Meliffi L
DOI：
10.1186/bcr2106
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Grimshaw MJ;Cooper L;Papazisis K;Coleman JA;Bohnenkamp HR;Chiapero-Stanke L;Taylor-Papadimitriou J;Burchell JM
通讯作者：
Burchell JM
影响因子：
11.5
作者：
Ge, Rongrong;Rajeev, Vaishali;Reiss, Michael
通讯作者：
Reiss, Michael