Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, College of Medicine, University of South Florida, Tampa, Florida, United States of America.
PLoS One. 2012;7(4):e35566. doi: 10.1371/journal.pone.0035566. Epub 2012 Apr 26.
MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB). Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family.
MKT-077 是一种花菁染料，已被证明可导致癌症特异性细胞死亡。然而，由于并发症，该化合物无法在临床试验之外使用。在这里，我们描述了 YM-1，它是 MKT-077 的一种衍生物。我们发现 YM-1 比 MKT-077 具有更高的细胞毒性和不同的定位。YM-1 在多种癌细胞系中表现出这种细胞毒性。这种毒性仅限于癌细胞系；永生化细胞模型不受影响。短暂应用 YM-1 被发现是无毒的。短暂用 YM-1 处理可恢复对难治性他莫昔芬耐药 MCF7 细胞模型的他莫昔芬敏感性。这种作用可能是由于雌激素受体α磷酸化的改变引起的，这是 Akt 水平（Akt/PKB）选择性降低所引发的结果。因此，对花菁染料支架进行修饰可能会提高其疗效和药代动力学特性。此外，对他莫昔芬敏感性的影响可能是该化合物家族的一个新用途。
