Department of Pharmacology, Guangxi Medical University, Nanning, Guangxi, 530021, China.
Department of Biology and Tennessee Center for Botanical Medicine Research, Middle Tennessee State University, Murfreesboro, TN, 37132, USA.
Sci Rep. 2017 Jul 27;7(1):6704. doi: 10.1038/s41598-017-07162-3.
Metastasis causes approximately 90% of breast cancer-related deaths in women. Previously, we have demonstrated that 2-dodecyl-6-methoxycyclohexa-2,5-diene- 1,4-dione (DMDD) remarkably inhibited the growth of human breast cancer cells with little toxicity. In this study, we investigated the toxicity and efficacy of DMDD to treat metastatic breast tumors using an in vivo mouse model of the 4T1 mammary carcinoma. DMDD caused no observable toxicity and significantly extended the survival of 4T1 tumor-bearing mice. DMDD effectively inhibited the growth of 4T1 cells in vitro, and suppressed the growth and metastasis of mammary tumor in vivo. The levels of inflammatory cytokines in the serum (TNF-α, IL-6, IL-12, TGF-β, and VEGF) were down regulated by DMDD. Immunohistochemical analysis demonstrated that the inhibition of tumor growth and metastasis was associated with activation of Bax, cleaved caspases-3 and -9, and down-regulation of Bcl-2, MMP-2 and -9, NF-κB and IκBα. We speculate that DMDD inhibits cytokine production in the tumor cells in mice, which leads to deactivation of NF-κB pathway, and consequently inhibits the expression of many anti-apoptosis and metastasis-promoting genes, such as Bcl-2 and MMPs. Collectively, our results demonstrate the potential of DMDD as a safe and effective antitumor agent in the treatment of late-stage breast cancer.
转移导致约 90%的女性乳腺癌相关死亡。此前，我们已经证明 2-十二烷基-6-甲氧基环己-2,5-二烯-1,4-二酮（DMDD）能显著抑制人乳腺癌细胞的生长，而毒性很小。在这项研究中，我们使用 4T1 乳腺癌的体内小鼠模型研究了 DMDD 治疗转移性乳腺癌的毒性和疗效。DMDD 未引起明显毒性，并显著延长了 4T1 荷瘤小鼠的存活期。DMDD 有效抑制了 4T1 细胞在体外的生长，并抑制了体内乳腺肿瘤的生长和转移。DMDD 下调了血清中炎症细胞因子的水平（TNF-α、IL-6、IL-12、TGF-β 和 VEGF）。免疫组化分析表明，肿瘤生长和转移的抑制与 Bax 的激活、裂解的 caspase-3 和 caspase-9 以及 Bcl-2、MMP-2 和 MMP-9、NF-κB 和 IκBα 的下调有关。我们推测 DMDD 抑制了小鼠肿瘤细胞中细胞因子的产生，导致 NF-κB 通路失活，从而抑制了许多抗凋亡和促进转移的基因的表达，如 Bcl-2 和 MMPs。总的来说，我们的结果表明 DMDD 具有作为治疗晚期乳腺癌的安全有效的抗肿瘤药物的潜力。
