Tobón-Cornejo Sandra, Vargas-Castillo Ariana, Juarez Mandy, Acevedo-Carabantes Joshua Ayork, Noriega Lilia G, Granados-Portillo Omar, Chávez-Blanco Alma, Morales-Bárcenas Rocío, Torres Nimbe, Tovar Armando R, Schcolnik-Cabrera Alejandro
Nutrition Physiology Department, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Life Sci. 2025 Jun 1;370:123562. doi: 10.1016/j.lfs.2025.123562. Epub 2025 Mar 14.
Breast cancer (BCa) is a heterogeneous disease, initially responsive to hormone therapy but often developing resistance to both hormonal and chemotherapy treatments. Novel therapeutic strategies are needed for drug-resistant BCa. Genistein, a phytoestrogen structurally similar to estrogen, competes with estrogen for receptor binding and exhibits anti-cancer effects. In this study, we investigated the cellular and metabolic impacts of genistein, alone or in combination with chemotherapy, in two human BCa cell lines-one estrogen receptor-positive (ER+) and one estrogen receptor-negative (ER-). We observed a strong synergistic effect on cell viability at low concentrations of genistein and chemotherapy, resulting in reduced clonogenic capacity and impaired cell migration. Genistein alone modulated cellular energy metabolism, notably reducing ATP production in MCF7 (ER+) cells. This metabolic shift was linked to a decreased dependence on fatty acids for energy, coupled with a decrease in the rate-limiting mitochondrial translocase CPT1 required for fatty acid oxidation, alongside with an increase in intracellular fatty acid levels. While the most significant changes occurred in ER+ cells, ER- cells also showed responses to genistein treatment. Collectively, our findings suggest that low genistein concentrations, in combination with conventional chemotherapy, induces synergistic anti-cancer effects, promoting cellular senescence.
乳腺癌（BCa）是一种异质性疾病，最初对激素治疗有反应，但常常会对激素和化疗产生耐药性。耐药性BCa需要新的治疗策略。染料木黄酮是一种结构与雌激素相似的植物雌激素，它与雌激素竞争受体结合并具有抗癌作用。在本研究中，我们研究了染料木黄酮单独或与化疗联合使用对两种人BCa细胞系（一种雌激素受体阳性（ER+）和一种雌激素受体阴性（ER-））的细胞和代谢影响。我们观察到在低浓度染料木黄酮和化疗时对细胞活力有强烈的协同作用，导致克隆形成能力降低和细胞迁移受损。单独使用染料木黄酮可调节细胞能量代谢，显著降低MCF7（ER+）细胞中的ATP产生。这种代谢转变与对脂肪酸能量依赖性降低有关，同时脂肪酸氧化所需的限速线粒体转位酶CPT1的速率降低，以及细胞内脂肪酸水平升高。虽然最显著的变化发生在ER+细胞中，但ER-细胞对染料木黄酮治疗也有反应。总的来说，我们的研究结果表明，低浓度染料木黄酮与传统化疗联合使用可诱导协同抗癌作用，促进细胞衰老。
