Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Int J Mol Sci. 2020 Jan 23;21(3):755. doi: 10.3390/ijms21030755.
Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood-brain barrier. Recent studies have revealed that penfluridol has significant anti-cancer activity in diverse tumors, such as metastatic breast cancer and glioblastoma. Here, we aim to identify the effect of low doses of penfluridol on tumor microenvironment and compare it with its effect on tumor cells. Although low concentration of penfluridol was not toxic for endothelial cells, it blocked angiogenesis in vitro and in vivo. In vitro, penfluridol inhibited VEGF-induced primary endothelial cell migration and tube formation, and in vivo, it blocked VEGF- and FGF-induced angiogenesis in the matrigel plug assay. VEGF-induced VEGFR2 phosphorylation and the downstream p38 and ERK signaling pathways were not affected in endothelial cells, although VEGF-induced Src and Akt activation were abrogated by penfluridol treatment. When cancer cells were treated with the same low concentration of penfluridol, basal Src activation levels were mildly impaired, thus impacting their cell migration and wound healing efficiency. The potential of cancer-induced paracrine effect on endothelial cells was explored, although that did not seem to be a player for angiogenesis. Overall, our data demonstrates that low penfluridol levels, similar to the ones clinically used for anti-psychotic conditions, suppress angiogenic efficiency in the tumor microenvironment.
转移被认为是癌症的主要负担，超过 90%的癌症相关死亡与之相关。肿瘤血管生成是导致肿瘤转移的主要过程之一。奋乃静是一种经典且常用的抗精神病药物，具有很强的血脑屏障穿透能力。最近的研究表明，奋乃静在多种肿瘤中具有显著的抗癌活性，如转移性乳腺癌和神经胶质瘤。在这里，我们旨在确定低剂量奋乃静对肿瘤微环境的影响，并将其与对肿瘤细胞的影响进行比较。尽管低浓度奋乃静对内皮细胞没有毒性，但它在体外和体内都能阻断血管生成。在体外，奋乃静抑制 VEGF 诱导的原代内皮细胞迁移和管形成，在体内，它阻断 VEGF 和 FGF 诱导的基质胶塞试验中的血管生成。虽然 VEGF 诱导的 VEGFR2 磷酸化和下游 p38 和 ERK 信号通路在内皮细胞中不受影响，但奋乃静处理阻断了 VEGF 诱导的Src 和 Akt 激活。当用相同的低浓度奋乃静处理癌细胞时，基础 Src 激活水平受到轻微损害，从而影响它们的细胞迁移和伤口愈合效率。虽然这似乎不是血管生成的一个因素，但我们探索了癌症诱导的旁分泌效应对内皮细胞的潜在影响。总之，我们的数据表明，低浓度奋乃静（类似于临床上用于抗精神病的浓度）可抑制肿瘤微环境中的血管生成效率。
