Manupati Kanakaraju, Dhoke Neha R, Debnath Tanusree, Yeeravalli Ragini, Guguloth Kalpana, Saeidpour Shahrzad, De Utpal Chandra, Debnath Sudhan, Das Amitava
Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
Academy of Scientific & Innovative Research, New Delhi, India.
FEBS J. 2017 Jun;284(12):1830-1854. doi: 10.1111/febs.14084. Epub 2017 May 16.
The recurrence of breast cancer in patients is a persistent challenge to the medical fraternity. Breast tumor contains a small population of cells with high tumor initiating and metastatic potential, known as cancer stem cells (CSCs), which are resistant to existing chemotherapeutics. CSCs contribute to the aggressiveness of triple negative breast cancers (TNBCs), thereby necessitating the identification of molecular targets on breast CSCs. TNBC cell line MDA-MB-231, in comparison with MCF-7, demonstrated a higher expression of epidermal growth factor receptor (EGFR). Thus, the naturally occurring flavanone, chrysin, with limited potential as a chemotherapeutic agent, was structurally modified by designing an analog with EGFR binding affinity using a molecular docking approach and subsequently synthesised. Chrysin analog CHM-09 and known EGFR inhibitors demonstrated a comparable anti-proliferative, anti-migratory activity along with the induction of apoptosis and cell cycle arrest in MDA-MB-231. Furthermore, sorted CD24 /CD44 -breast CSCs and CD24 -breast cancer cells from MDA-MB-231 demonstrated a markedly high expression of EGFR in the former than in the latter. CHM-09 and EGFR inhibitors could perturb EGF-induced EGFR signalling of breast CSC proliferation, migration, mammosphere formation and mesenchymal tri-lineage differentiation. CHM-09 or EGFR inhibitors not only led to inactivation of EGFR downstream signalling pathways such as Akt, extracellular signal regulated kinase and signal transducer and activator of transcription 3, but also induction of mesenchymal-epithelial transition as confirmed by decreased N-cadherin and increased E-cadherin expression. Finally, combinatorial treatment of EGFR inhibitors and doxorubicin led to significant increase in breast CSCs responsiveness to a chemotherapeutic drug. The results of the present study suggest that EGFR is a therapeutic target in breast CSCs and that abrogation of EGFR signalling along with chemotherapeutic drugs is an effective approach against breast cancer.
乳腺癌患者的复发一直是医学界面临的挑战。乳腺肿瘤中含有一小部分具有高肿瘤起始和转移潜能的细胞，即癌症干细胞（CSCs），它们对现有的化疗药物具有抗性。癌症干细胞导致三阴性乳腺癌（TNBCs）具有侵袭性，因此有必要确定乳腺癌症干细胞上的分子靶点。与MCF-7相比，TNBC细胞系MDA-MB-231中表皮生长因子受体（EGFR）的表达更高。因此，天然存在的黄酮类化合物白杨素作为一种化疗药物潜力有限，通过分子对接方法设计一种具有EGFR结合亲和力的类似物对其进行结构修饰，随后进行合成。白杨素类似物CHM-09与已知的EGFR抑制剂在MDA-MB-231中表现出相当的抗增殖、抗迁移活性，同时诱导细胞凋亡和细胞周期停滞。此外，从MDA-MB-231中分选出来的CD24⁻/CD44⁺乳腺癌症干细胞和CD24⁻乳腺癌细胞显示，前者中EGFR的表达明显高于后者。CHM-09和EGFR抑制剂可干扰表皮生长因子（EGF）诱导的乳腺癌症干细胞增殖、迁移、乳腺球形成和间充质三系分化的EGFR信号传导。CHM-09或EGFR抑制剂不仅导致EGFR下游信号通路如Akt、细胞外信号调节激酶和信号转导子及转录激活子3失活，还通过降低N-钙黏蛋白表达和增加E-钙黏蛋白表达证实诱导了间充质-上皮转化。最后，EGFR抑制剂与阿霉素联合治疗导致乳腺癌症干细胞对化疗药物的反应性显著增加。本研究结果表明，EGFR是乳腺癌症干细胞的一个治疗靶点，消除EGFR信号传导并联合化疗药物是对抗乳腺癌的有效方法。
