Rational Drug Design of Targeted and Enzyme-Cleavable Vitamin E Analogs as a Neoadjuvant to Chemotherapy: In Vitro and In Vivo Evaluation on Reduction of the Cardiotoxicity Side Effect of Doxorubicin.
Rational Drug Design of Targeted and Enzyme-Cleavable Vitamin E Analogs as a Neoadjuvant to Chemotherapy: In Vitro and In Vivo Evaluation on Reduction of the Cardiotoxicity Side Effect of Doxorubicin.
复制标题
DOI：
10.1021/acsptsci.2c00091
复制
发表时间：
2023-02
影响因子：
6
通讯作者：
Raghu S Pandurangi;Orsolya Cseh;H. A. Luchman;Cynthia X. Ma;S. N. Senadheera;M. Forrest
中科院分区：
文献类型：
--
作者：
Raghu S Pandurangi;Orsolya Cseh;H. A. Luchman;Cynthia X. Ma;S. N. Senadheera;M. Forrest
传统的药物设计着眼于特定的生物靶点，即癌细胞过度表达特定受体或生物标记物的地方。癌细胞通过激活生存途径和/或下调细胞死亡途径来规避干预，以求生存。肿瘤细胞凋亡通路的先验激活(AAAPT)是一种新的肿瘤增敏技术，它通过靶向肿瘤细胞脱敏过程中涉及的特定生存通路，使对当前治疗反应不佳的肿瘤细胞增敏，并试图在癌细胞中选择性地恢复它们，而不是正常细胞。合成、表征和研究了几种维生素E衍生物(AMP-001、AMP-002、AMP-003和AMP-004)的抗肿瘤特性及其与标准化疗药物阿霉素在体外对包括脑癌细胞在内的多种癌细胞的协同作用。初步研究表明，AAAPT药物(A)降低了脑瘤干细胞的侵袭潜力，(B)与联邦药物申请批准的阿霉素有协同作用，(C)提高了阿霉素在三阴性乳腺癌大鼠模型中的治疗指数，与治疗剂量下的单独心脏毒性阿霉素相比，保留了心功能。AAAPT方法的优点是通过靶向、肿瘤特异性组织蛋白酶B可切割的连接物和聚乙二醇化技术，选择性地抑制癌细胞的生存途径和激活细胞死亡途径，以提高生物利用度。我们建议AAAPT药物作为化疗的新辅助药物，而不是单独治疗，这被证明在扩大阿霉素的治疗指数并使其在较低剂量下起作用方面是有效的。
Traditional drug design focuses on specific biological targets where specific receptors or biomarkers are overexpressed by cancer cells. Cancer cells circumvent the interventions by activating survival pathways and/or downregulating cell death pathways for their survival. A priori activation of apoptosis pathways of tumor (AAAPT) is a novel tumor-sensitizing technology that sensitizes tumor cells that are not responding well to the current treatments by targeting specific survival pathways involved in the desensitization of tumor cells and tries to revive them selectively in cancer cells, sparing normal cells. Several vitamin E derivatives (AMP-001, AMP-002, AMP-003, and AMP-004) were synthesized, characterized, and studied for their anti-tumorigenic properties and their synergistic potential with the standard chemotherapy doxorubicin in various cancer cells including brain cancer stem cells in vitro. Preliminary studies revealed that AAAPT drugs (a) reduced the invasive potential of brain tumor stem cells, (b) synergized with Federal Drug Application-approved doxorubicin, and (c) enhanced the therapeutic index of doxorubicin in the triple-negative breast cancer tumor rat model, preserving the ventricular function compared to cardiotoxic doxorubicin alone at therapeutic dose. The AAAPT approach has the advantage of inhibiting survival pathways and activating cell death pathways selectively in cancer cells by using targeting, linkers cleavable by tumor-specific Cathepsin B, and PEGylation technology to enhance the bioavailability. We propose AAAPT drugs as a neoadjuvant to chemotherapy and not as stand-alone therapy, which is shown to be effective in expanding the therapeutic index of doxorubicin and making it work at lower doses.