Czech Academy of Sciences, Institute of Biophysics, Kralovopolska 135, 61265, Brno, Czech Republic.
Departamento de Química Inorgánica, Universidad de Murcia, and Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30071, Murcia, Spain.
Chemistry. 2021 Jun 10;27(33):8547-8556. doi: 10.1002/chem.202100568. Epub 2021 May 14.
A cyclometalated Ir complex conjugated to a far-red-emitting coumarin, Ir -COUPY (3), was recently shown as a very promising photosensitizer suitable for photodynamic therapy of cancer. Therefore, the primary goal of this work was to deepen knowledge on the mechanism of its photoactivated antitumor action so that this information could be used to propose a new class of compounds as drug candidates for curing very hardly treatable human tumors, such as androgen resistant prostatic tumors of metastatic origin. Conventional anticancer chemotherapies exhibit several disadvantages, such as limited efficiency to target cancer stem cells (CSCs), which are considered the main reason for chemotherapy resistance, relapse, and metastasis. Herein, we show, using DU145 tumor cells, taken as the model of hormone-refractory and aggressive prostate cancer cells resistant to conventional antineoplastic drugs, that the photoactivated conjugate 3 very efficiently eliminates both prostate bulk (differentiated) and prostate hardly treatable CSCs simultaneously and with a similar efficiency. Notably, the very low toxicity of Ir -COUPY conjugate in the prostate DU145 cells in the dark and its pronounced selectivity for tumor cells compared with noncancerous cells could result in low side effects and reduced damage of healthy cells during the photoactivated therapy by this agent. Moreover, the experiments performed with the 3D spheroids formed from DU145 CSCs showed that conjugate 3 can penetrate the inner layers of tumor spheres, which might markedly increase its therapeutic effect. Also interestingly, this conjugate induces apoptotic cell death in prostate cancer DU145 cells associated with calcium signaling flux in these cells and autophagy. To the best of our knowledge, this is the first study demonstrating that a photoactivatable metal-based compound is an efficient agent capable of killing even hardly treatable CSCs.
一种与远红发射香豆素偶联的环金属化 Ir 配合物 Ir-COUPY（3），最近被证明是一种很有前途的光动力治疗癌症的光敏剂。因此，这项工作的主要目标是深入了解其光激活抗肿瘤作用的机制，以便利用这些信息提出一类新的化合物作为候选药物，用于治疗非常难以治疗的人类肿瘤，如转移性雄激素抵抗前列腺肿瘤。传统的抗癌化疗有几个缺点，例如对癌症干细胞（CSCs）的靶向效率有限，CSCs 被认为是化疗耐药、复发和转移的主要原因。在此，我们使用 DU145 肿瘤细胞作为模型，研究了激素难治性和侵袭性前列腺癌细胞对传统抗肿瘤药物的耐药性，表明光激活偶联物 3 非常有效地同时且以相似的效率消除前列腺肿瘤的大部分（分化）和难以治疗的 CSCs。值得注意的是，Ir-COUPY 偶联物在前列腺 DU145 细胞中在黑暗中的毒性非常低，并且与非癌细胞相比，其对肿瘤细胞的选择性非常高，这可能导致该药物的光激活治疗的副作用低且对健康细胞的损伤小。此外，用 DU145 CSCs 形成的 3D 球体进行的实验表明，偶联物 3 可以穿透肿瘤球体的内层，这可能显著增加其治疗效果。同样有趣的是，这种偶联物诱导前列腺癌 DU145 细胞凋亡，与这些细胞中的钙信号流和自噬有关。据我们所知，这是第一项证明光激活金属基化合物是一种有效药物，能够杀死甚至难以治疗的 CSCs 的研究。
