The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
Molecules. 2023 Apr 23;28(9):3662. doi: 10.3390/molecules28093662.
Paclitaxel-triethylenetetramine hexaacetic acid conjugate (PTX-TTHA), a novel semi-synthetic taxane, is designed to improve the water solubility and cosolvent toxicity of paclitaxel in several aminopolycarboxylic acid groups. In this study, the in vitro and in vivo antitumor effects and mechanisms of PTX-TTHA against triple-negative breast cancer (TNBC) and its intravenous toxicity were evaluated. Results showed the water solubility of PTX-TTHA was greater than 5 mg/mL, which was about 7140-fold higher than that of paclitaxel (<0.7 µg/mL). PTX-TTHA (10-10 nmol/L) could significantly inhibit breast cancer proliferation and induce apoptosis by stabilizing microtubules and arresting the cell cycle in the G2/M phase in vitro, with its therapeutic effect and mechanism similar to paclitaxel. However, when the MDA-MB-231 cell-derived xenograft (CDX) tumor model received PTX-TTHA (13.73 mg/kg) treatment once every 3 days for 21 days, the tumor inhibition rate was up to 77.32%. Furthermore, PTX-TTHA could inhibit tumor proliferation by downregulating Ki-67, and induce apoptosis by increasing pro-apoptotic proteins (Bax, cleaved caspase-3) and TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and reducing anti-apoptotic protein (Bcl-2). Moreover, PTX-TTHA demonstrated no sign of acute toxicity on vital organs, hematological, and biochemical parameters at the limit dose (138.6 mg/kg, i.v.). Our study indicated that PTX-TTHA showed better water solubility than paclitaxel, as well as comparable in vitro and in vivo antitumor activity in TNBC models. In addition, the antitumor mechanism of PTX-TTHA was related to microtubule regulation and apoptosis signaling pathway activation.
紫杉醇三乙烯四胺六乙酸酯缀合物（PTX-TTHA）是一种新型的半合成紫杉烷，旨在通过在几个氨基多羧酸基团中改善紫杉醇的水溶性和助溶剂毒性。在这项研究中，评估了 PTX-TTHA 对三阴性乳腺癌（TNBC）的体外和体内抗肿瘤作用及其静脉毒性及其作用机制。结果表明，PTX-TTHA 的水溶性大于 5mg/mL，约为紫杉醇（<0.7μg/mL）的 7140 倍。PTX-TTHA（10-10nmol/L）可通过稳定微管和将细胞周期阻滞在 G2/M 期来显著抑制乳腺癌的增殖并诱导细胞凋亡，其治疗效果和机制与紫杉醇相似。然而，当 MDA-MB-231 细胞衍生的异种移植（CDX）肿瘤模型接受 PTX-TTHA（13.73mg/kg）每 3 天治疗一次，共 21 天时，肿瘤抑制率高达 77.32%。此外，PTX-TTHA 可以通过下调 Ki-67 来抑制肿瘤增殖，并通过增加促凋亡蛋白（Bax、cleaved caspase-3）和 TdT 介导的 dUTP 缺口末端标记（TUNEL）阳性凋亡细胞以及减少抗凋亡蛋白（Bcl-2）来诱导细胞凋亡。此外，在极限剂量（138.6mg/kg，iv.）下，PTX-TTHA 对重要器官、血液学和生化参数均无明显急性毒性迹象。我们的研究表明，PTX-TTHA 比紫杉醇具有更好的水溶性，并且在 TNBC 模型中具有相当的体外和体内抗肿瘤活性。此外，PTX-TTHA 的抗肿瘤机制与微管调节和细胞凋亡信号通路激活有关。
