Department of Molecular Biology and Biotechnology, and Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai University, 5-7 Clinicilor Street, 400006, Cluj-Napoca, Romania.
Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, 29 Biedersteiner Street, 80802, Munich, Germany.
Sci Rep. 2021 Nov 11;11(1):22102. doi: 10.1038/s41598-021-01284-5.
Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to the development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo, with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s.c. B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy almost totally inhibited (> 90%) the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and simultaneous induction of a pro-apoptotic state of tumor cells in the tumor microenvironment (TME). These effects were accompanied by the partial re-education of TAMs towards an M1 phenotype and augmented by combined therapy-induced suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the TME, by suppressing its most important malignant biological capabilities.
抗血管生成疗法在黑色素瘤患者中尚未转化为有意义的临床获益，这是由于癌细胞产生了药物诱导的耐药性，主要由缺氧诱导因子 1α（HIF-1α）过表达和肿瘤相关巨噬细胞（TAMs）介导的氧化应激增强引起。我们之前的研究表明，辛伐他汀（SIM）和 5,6-二甲基黄嘌呤-4-乙酸（DMXAA）联合作用于体外黑色素瘤模型具有协同的抗肿瘤作用，可通过抑制黑色素瘤细胞的侵袭表型和抑制 TAMs 介导的血管生成来发挥作用。因此，我们利用长循环脂质体（LCL）优越的肿瘤靶向能力，将 SIM 和 DMXAA 有效地递送至 B16.F10 黑色素瘤体内，最终目的是改善抗血管生成治疗的效果。因此，我们评估了这种新型联合肿瘤靶向治疗对皮下 B16.F10 鼠黑色素瘤生长和肿瘤发生发展中关键标志物产生的影响。我们的结果表明，联合脂质体治疗几乎完全抑制（>90%）黑色素瘤肿瘤的生长，这是由于 LCL-SIM 增强了 LCL-DMXAA 的抗血管生成作用，同时诱导肿瘤细胞在肿瘤微环境（TME）中发生促凋亡状态。这些作用伴随着 TAMs 向 M1 表型的部分重新教育，并通过联合治疗诱导的主要侵袭和转移促进物（HIF-1α、pAP-1 c-Jun 和 MMPs）的抑制而增强。因此，这种新型治疗方法有可能通过抑制 TME 最重要的恶性生物学能力来重塑 TME。
