Pandurangi Raghu S, Cseh Orsolya, Luchman Hema Artee, Ma Cynthia Xiuguang, Senadheera Sanjeewa N, Forrest Marcus Laird
Sci-Engi-Medco Solutions Inc. (SEMCO), 573, Lexington Landing Pl, St. Charles, Missouri 63303, United States.
HRIC 2A25, 3330 Hospital Drive NW, Calgary, AB T2N 4N, Canada.
ACS Pharmacol Transl Sci. 2023 Feb 6;6(3):372-386. doi: 10.1021/acsptsci.2c00091. eCollection 2023 Mar 10.
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 . 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.
传统药物设计聚焦于特定的生物学靶点，即癌细胞过度表达特定受体或生物标志物的地方。癌细胞通过激活生存途径和/或下调细胞死亡途径以存活来规避干预。肿瘤凋亡途径的先验激活（AAAPT）是一种新型的肿瘤致敏技术，它通过靶向参与肿瘤细胞脱敏的特定生存途径，使对当前治疗反应不佳的肿瘤细胞致敏，并试图在癌细胞中选择性地使其恢复活力，同时使正常细胞不受影响。合成、表征并研究了几种维生素E衍生物（AMP - 001、AMP - 002、AMP - 003和AMP - 004）在包括脑癌干细胞在内的各种癌细胞中的抗肿瘤特性及其与标准化疗药物阿霉素的协同潜力。初步研究表明，AAAPT药物（a）降低了脑肿瘤干细胞的侵袭潜力，（b）与美国食品药品监督管理局批准的阿霉素协同作用，并且（c）在三阴性乳腺癌肿瘤大鼠模型中提高了阿霉素的治疗指数，与单独使用治疗剂量的具有心脏毒性的阿霉素相比，保留了心室功能。AAAPT方法的优势在于通过使用靶向、可被肿瘤特异性组织蛋白酶B切割的连接子以及聚乙二醇化技术来提高生物利用度，从而在癌细胞中选择性地抑制生存途径并激活细胞死亡途径。我们提出将AAAPT药物作为化疗的新辅助药物，而不是单独的治疗方法，已证明其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。
