McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, 3640 University Street, Montreal, QC, H3A 0C7, Canada.
Oral Pathology Department, Faculty of Dentistry, Mansoura University, Mansoura, Egypt.
Med Oncol. 2018 Aug 4;35(9):124. doi: 10.1007/s12032-018-1186-4.
The efficacy of cisplatin (CIS) and 5-fluorouracil (5-FU) against squamous cell carcinomas of the head and neck (SCCHN) remains restricted due to their severe toxic side effects on non-cancer (normal) tissues. Recently, the broccoli extract sulforaphane (SF) was successfully tested as a combination therapy to target cancer cells. However, the effect of lower doses of CIS or 5-FU combined with SF on SCCHN remained unknown. This study tested the chemotherapeutic efficacies of SF combined with much lower doses of CIS or 5-FU against SCCHN cells aiming to reduce cytotoxicity to normal cells. Titrations of SF standalone or in combination with CIS and 5-FU were tested on SCCHN human cell lines (SCC12 and SCC38) and non-cancerous human cells (fibroblasts, gingival, and salivary cells). Concentrations of SF tested were comparable to those found in the plasma following ingestion of fresh broccoli sprouts. The treatment effects on cell viability, proliferation, DNA damage, apoptosis, and gene expression were measured. SF reduced SCCHN cell viability in a time- and dose-dependent manner. SF-combined treatment increased the cytotoxic activity of CIS by twofolds and of 5-FU by tenfolds against SCCHN, with no effect on non-cancerous cells. SF-combined treatment inhibited SCCHN cell clonogenicity and post-treatment DNA repair. SF increased SCCHN apoptosis and this mechanism was due to a down-regulation of BCL2 and up-regulation of BAX, leading to an up-regulation of Caspase3. In conclusion, combining SF with low doses of CIS or 5-FU increased cytotoxicity against SCCHN cells, while having minimal effects on normal cells.
顺铂（CIS）和 5-氟尿嘧啶（5-FU）治疗头颈部鳞状细胞癌（SCCHN）的疗效仍然受到限制，因为它们对非癌症（正常）组织有严重的毒性副作用。最近，西兰花提取物萝卜硫素（SF）已成功被测试为联合治疗方法，以靶向癌细胞。然而，CIS 或 5-FU 与 SF 的较低剂量联合对 SCCHN 的作用仍不清楚。本研究旨在降低对正常细胞的细胞毒性，测试 SF 与 CIS 或 5-FU 的较低剂量联合对 SCCHN 细胞的化疗疗效。SF 单独或与 CIS 和 5-FU 联合测试了 SCCHN 人细胞系（SCC12 和 SCC38）和非癌细胞（成纤维细胞、牙龈和唾液细胞）的化疗效果。测试的 SF 浓度与摄入新鲜西兰花芽后血浆中发现的浓度相当。测量了 SF 对细胞活力、增殖、DNA 损伤、细胞凋亡和基因表达的治疗效果。SF 以时间和剂量依赖的方式降低了 SCCHN 细胞活力。SF 联合治疗使 CIS 的细胞毒性增加了两倍，使 5-FU 的细胞毒性增加了十倍，对非癌细胞没有影响。SF 联合治疗抑制了 SCCHN 细胞集落形成和治疗后 DNA 修复。SF 增加了 SCCHN 细胞凋亡，这种机制是由于 BCL2 的下调和 BAX 的上调，导致 Caspase3 的上调。总之，SF 与低剂量 CIS 或 5-FU 联合使用可提高对 SCCHN 细胞的细胞毒性，而对正常细胞的影响最小。
