School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Int J Mol Sci. 2022 Apr 27;23(9):4814. doi: 10.3390/ijms23094814.
There is a need for agents that eliminate cancer stem cells, which sustain cancer and are also largely responsible for disease relapse and metastasis. Conventional chemotherapeutics and radiotherapy are often highly effective against the bulk of cancer cells, which are proliferating, but spare cancer stem cells. Therapeutics that target cancer stem cells may also provide a cure for cancer. There are two rationales for targeting the retinoic acid receptor (RAR)γ. First, RARγ is expressed selectively within primitive cells. Second, RARγ is a putative oncogene for a number of human cancers, including cases of acute myeloid leukemia, cholangiocarcinoma, and colorectal, renal and hepatocellular carcinomas. Prostate cancer cells depend on active RARγ for their survival. Antagonizing all RARs caused necroptosis of prostate and breast cancer stem cell-like cells, and the cancer stem cells that gave rise to neurospheres from pediatric patients' primitive neuroectodermal tumors and an astrocytoma. As tested for prostate cancer, antagonizing RARγ was sufficient to drive necroptosis. Achieving cancer-selectively is a longstanding paradigm for developing new treatments. The normal prostate epithelium was less sensitive to the RARγ antagonist and pan-RAR antagonist than prostate cancer cells, and fibroblasts and blood mononuclear cells were insensitive. The RARγ antagonist and pan-RAR antagonist are promising new cancer therapeutics.
需要能够消灭癌症干细胞的药物，因为这些细胞能够维持肿瘤生长，而且在很大程度上是导致疾病复发和转移的原因。传统的化疗和放疗通常对增殖中的大量癌细胞非常有效，但会放过癌症干细胞。针对癌症干细胞的治疗方法也可能为癌症提供治愈的可能。针对视黄酸受体 (RAR)γ 的治疗有两个合理的理由。首先，RARγ 在原始细胞中选择性表达。其次，RARγ 是许多人类癌症的潜在致癌基因，包括急性髓细胞白血病、胆管癌、结直肠癌、肾癌和肝癌。前列腺癌细胞的存活依赖于活跃的 RARγ。拮抗所有的 RAR 会导致前列腺癌和乳腺癌干细胞样细胞以及源自儿科患者原始神经外胚层肿瘤和星形细胞瘤的神经球的坏死。在前列腺癌的测试中，拮抗 RARγ 足以引发坏死。选择性地实现癌症治疗是开发新疗法的长期范例。与前列腺癌细胞相比，正常前列腺上皮对 RARγ 拮抗剂和泛 RAR 拮抗剂的敏感性较低，而成纤维细胞和血液单核细胞则不敏感。RARγ 拮抗剂和泛 RAR 拮抗剂是很有前途的新型癌症治疗药物。
