Institute for Genetic and Biomedical Research (IRGB), National Research Council of Italy (CNR), Traversa la Crucca 3, 07100 Sassari, Italy.
Institute of Biomolecular Chemistry (ICB), National Research Council of Italy (CNR), Traversa la Crucca 3, 07100 Sassari, Italy.
Int J Mol Sci. 2021 May 26;22(11):5636. doi: 10.3390/ijms22115636.
Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat despite recent advances in targeted and immune therapies. About 50% of advanced melanoma do not benefit of such therapies, and novel treatments are requested. Curcumin and its analogs have shown good anticancer properties and are being considered for use in combination with or sequence to recent therapies to improve patient outcomes. Our group previously published the synthesis and anticancer activity characterization of a novel curcumin-related compound against melanoma and neuroblastoma cells (D6). Here, two hydroxylated biphenyl compounds-namely, compounds and -were selected among a small collection of previously screened C2-symmetric hydroxylated biphenyls structurally related to D6 and curcumin, showing the best antitumor potentiality against melanoma cells (IC values of 1.7 ± 0.5 μM for and 2.0 ± 0.7 μM for ) and no toxicity of normal fibroblasts up to 32 µM. Their antiproliferative activity was deeply characterized on five melanoma cell lines by performing dose-response and clonal growth inhibition assays, which revealed long-lasting and irreversible effects for both compounds. Apoptosis induction was ascertained by the annexin V and TUNEL assays, whereas Western blotting showed caspase activation and PARP cleavage. A cell cycle analysis, following cell treatments with either compound or , highlighted an arrest in the G2/M transition. Taking all this evidence together, and were shown to be good candidates as lead compounds to develop new anticancer drugs against malignant melanoma.
黑色素瘤是最致命的皮肤癌之一，尽管近年来靶向治疗和免疫疗法取得了进展，但它仍然是最难治疗的癌症之一。大约 50%的晚期黑色素瘤患者不能从这些治疗中获益，因此需要新的治疗方法。姜黄素及其类似物已显示出良好的抗癌特性，正在考虑与最近的治疗方法联合或序贯使用，以改善患者的治疗效果。我们的小组之前发表了一种新型姜黄素相关化合物（D6）对黑色素瘤和神经母细胞瘤的合成和抗癌活性特征。在这里，在一组以前筛选的结构上与 D6 和姜黄素相关的 C2 对称羟基化联苯中，选择了两种羟基化联苯化合物（化合物 和 ），它们对黑色素瘤细胞显示出最好的抗肿瘤潜力（对黑色素瘤细胞的 IC 值分别为 1.7±0.5 μM 和 2.0±0.7 μM），而在 32 μM 时对正常成纤维细胞没有毒性。通过进行剂量反应和克隆生长抑制实验，对这两种化合物在五种黑色素瘤细胞系中的增殖活性进行了深入研究，结果表明这两种化合物均具有持久和不可逆的作用。通过 Annexin V 和 TUNEL 检测证实了细胞凋亡的诱导，而 Western blot 显示了半胱天冬酶的激活和 PARP 的切割。用两种化合物之一（ 或 ）处理细胞后进行细胞周期分析，显示 G2/M 期转换停滞。综合所有这些证据， 和 被证明是开发针对恶性黑色素瘤的新型抗癌药物的良好候选物。
