Turner Katherine A, Manouchehri Jasmine M, Kalafatis Michael
Department of Chemistry, Cleveland State University.
Center for Gene Regulation in Health and Disease (GRHD).
Melanoma Res. 2018 Aug;28(4):277-285. doi: 10.1097/CMR.0000000000000447.
Malignant melanoma is the most commonly diagnosed skin cancer associated with a high rate of metastasis. Low-stage melanoma is easily treated, but metastatic malignant melanoma is an extremely treatment-resistant malignancy with low survival rates. The application of recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) for the treatment of metastatic malignant melanoma holds considerable promise because of its selective proapoptotic activity towards cancer cells and not nontransformed cells. Unfortunately, the clinical utilization of rhTRAIL has been terminated due to the resistance of many cancer cells to undergo apoptosis in response to rhTRAIL. However, rhTRAIL-resistance can be abrogated through the cotreatment with compounds derived from 'Mother Nature' such as quercetin that can modulate cellular components responsible for rhTRAIL-resistance. Here, we show that rhTRAIL-resistant malignant melanomas are sensitized by quercetin. Quercetin action is manifested by the upregulation of rhTRAIL-binding receptors DR4 and DR5 on the surface of cancer cells and by increased rate of the proteasome-mediated degradation of the antiapoptotic protein FLIP. Our data provide for a new efficient and nontoxic treatment of malignant melanoma.
恶性黑色素瘤是最常被诊断出的皮肤癌，其转移率很高。低分期黑色素瘤易于治疗，但转移性恶性黑色素瘤是一种极具治疗抗性的恶性肿瘤，生存率很低。重组人肿瘤坏死因子相关凋亡诱导配体（rhTRAIL）用于治疗转移性恶性黑色素瘤具有很大前景，因为它对癌细胞具有选择性促凋亡活性，而对未转化细胞则无此作用。不幸的是，由于许多癌细胞对rhTRAIL诱导的凋亡具有抗性，rhTRAIL的临床应用已被终止。然而，通过与源自“大自然”的化合物（如槲皮素）联合治疗，可以消除rhTRAIL抗性，槲皮素能够调节导致rhTRAIL抗性的细胞成分。在此，我们表明槲皮素可使对rhTRAIL耐药的恶性黑色素瘤敏感化。槲皮素的作用表现为癌细胞表面rhTRAIL结合受体DR4和DR5的上调，以及抗凋亡蛋白FLIP蛋白酶体介导降解速率的增加。我们的数据为恶性黑色素瘤提供了一种新的高效无毒治疗方法。
