Clinical Pharmacy Department, National Cancer Institute, Cairo University, Cairo, Egypt.
Clinical Pharmacy Department, School of Pharmacy, Newgiza University, Giza, Egypt.
Sci Rep. 2024 Jan 2;14(1):41. doi: 10.1038/s41598-023-50478-6.
Although cyclophosphamide (CTX) has been used for recurrent or metastatic head and neck cancers, resistance is usually expected. Thus, we conducted this study to examine the effect of adding all-trans retinoic acid (ATRA) to CTX, to increase efficacy of CTX and reduce the risk of resistance developed. In this study, we investigated the combined effect of ATRA and CTX on the expression of apoptotic and angiogenesis markers in oropharyngeal carcinoma cell line (NO3), and the possible involved mechanisms. ATRA and CTX in combination significantly inhibited the proliferation of NO3 cells. Lower dose of CTX in combination with ATRA exhibited significant cytotoxicity than that of CTX when used alone, implying lower expected toxicity. Results showed that ATRA and CTX modulated oxidative stress; increased NOx and MDA, reduced GSH, and mRNA expression of Cox-2, SIRT1 and AMPK. Apoptosis was induced through elevating mRNA expressions of Bax and PAR-4 and suppressing that of Bcl-xl and Bcl-2, parallel with increased caspases 3 and 9 and decreased VEGF, endothelin-1 and CTGF levels. The primal action of the combined regimen on inflammatory signaling highlights its impact on cell death in NO3 cell line which was mediated by oxidative stress associated with apoptosis and suppression of angiogenesis.
虽然环磷酰胺 (CTX) 已被用于复发性或转移性头颈部癌症，但通常预计会产生耐药性。因此，我们进行了这项研究，以检验在 CTX 中加入全反式视黄酸 (ATRA) 的效果，以提高 CTX 的疗效并降低产生耐药性的风险。在这项研究中，我们研究了 ATRA 和 CTX 联合对口腔咽癌细胞系 (NO3) 中凋亡和血管生成标志物表达的影响，以及可能涉及的机制。ATRA 和 CTX 联合显著抑制了 NO3 细胞的增殖。与单独使用 CTX 相比，联合使用较低剂量的 CTX 表现出显著的细胞毒性，这意味着预期的毒性较低。结果表明，ATRA 和 CTX 调节氧化应激；增加 NOx 和 MDA，减少 GSH，以及 Cox-2、SIRT1 和 AMPK 的 mRNA 表达。通过上调 Bax 和 PAR-4 的 mRNA 表达和下调 Bcl-xl 和 Bcl-2 的表达来诱导细胞凋亡，同时增加 caspase 3 和 9 的表达，降低 VEGF、内皮素-1 和 CTGF 的水平。联合方案对炎症信号的初步作用突出了其对 NO3 细胞系细胞死亡的影响，这是通过与凋亡和血管生成抑制相关的氧化应激介导的。
