Abou-Shanab Ahmed M, Shouman Shaimaa, Hussein Alaa E, Gaser Ola A, Magdy Shireen, Ashraf Eman, Salah Radwa Ayman, Idris Omaima, El-Badri Nagwa
Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12578, Egypt.
Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt.
BMC Cancer. 2025 Jun 19;25(1):1021. doi: 10.1186/s12885-025-14442-z.
Doxorubicin (DOX) remains a mainstay for neuroblastoma (NB) treatment, but side effects hamper efficacy. We previously showed that DOX induces SH-SY5Y NB cell angiogenesis via the PHD-2/HIF-1α axis. Adjuvant therapies offer a promising avenue to improved outcomes. Human amniotic membrane (hAM) extract (hAME) consists of various proteins that exhibit anti-cancer and anti-angiogenic properties. This study investigates hAME as a potential adjuvant for targeting NB angiogenesis when combined with DOX.
We used cellular, molecular, and biochemical assays to evaluate the antitumorigenic activities of hAME + DOX (D + E) treatment across key hallmarks of SH-SY5Y NB progression: proliferation, cell cycle, angiogenesis, invasiveness, differentiation, and cellular bioenergetics.
D + E treatment significantly suppressed SH-SY5Y cell proliferation, induced cell cycle perturbations, and reduced viability, while protecting bone marrow stem cells and human skin fibroblast normal cells. D + E treatment also countered SH-SY5Y cell invasiveness and promoted a favorable mesenchymal-to-epithelial transition (MET). Importantly, D + E treatment modulated the SH-SY5Y cellular respiration, evidenced by halted glycolytic metabolism, potentially influencing a shift towards oxidative phosphorylation and boosted urea cycle progression. Mechanistically, D + E abrogated DOX's pro-angiogenic effects and inhibited SH-SY5Y cells' neo-vascularization in a chick embryo model.
These findings suggest hAME as a promising adjuvant therapy for NB, potentially offering an effective and safe treatment strategy by targeting multiple hallmarks of NB.
多柔比星（DOX）仍是神经母细胞瘤（NB）治疗的主要药物，但副作用会影响疗效。我们之前表明，DOX通过PHD-2/HIF-1α轴诱导SH-SY5Y NB细胞血管生成。辅助治疗为改善治疗结果提供了一条有前景的途径。人羊膜（hAM）提取物（hAME）由多种具有抗癌和抗血管生成特性的蛋白质组成。本研究调查hAME与DOX联合使用时作为靶向NB血管生成的潜在辅助药物的效果。
我们使用细胞、分子和生化分析方法，评估hAME + DOX（D + E）治疗对SH-SY5Y NB进展的关键特征（增殖、细胞周期、血管生成、侵袭性、分化和细胞生物能量学）的抗肿瘤活性。
D + E治疗显著抑制SH-SY5Y细胞增殖，诱导细胞周期紊乱并降低细胞活力，同时保护骨髓干细胞和人皮肤成纤维细胞等正常细胞。D + E治疗还对抗SH-SY5Y细胞的侵袭性，并促进有利的间充质向上皮转化（MET）。重要的是，D + E治疗调节了SH-SY5Y细胞的呼吸作用，表现为糖酵解代谢停止，这可能影响向氧化磷酸化的转变并促进尿素循环进程。从机制上讲，D + E消除了DOX的促血管生成作用，并在鸡胚模型中抑制了SH-SY5Y细胞的新生血管形成。
这些发现表明hAME作为NB的一种有前景的辅助治疗药物，可能通过靶向NB的多个特征提供一种有效且安全的治疗策略。
