Galangin inhibits the development of breast cancer through PTEN/AKT signaling pathway and increases the anti-tumor activity of trastuzumab
Breast cancer (BC) is the leading cause of cancer-related deaths in women. Chemotherapy is one of the main treatment strategies for breast cancer. Trastuzumab is a humanized monoclonal antibody derived from recombinant DNA. It blocks the growth of breast cancer cancer cells by targeting Her-2 (human epidermal growth factor 2), and at the same time stimulates the body’s immune cells to kill cancer cells. However, many breast cancer patients have no response to the initial targeted therapy, or acquired and cross resistance occur in subsequent treatment, leading to poor prognosis and high mortality in clinical patients. Therefore, there is an urgent need to develop new therapies for breast cancer, or effective synergists or adjuvant drug combination therapy to improve the cure rate.

With the rapid development of traditional Chinese medicine research, the anti-cancer and sensitizing effects of traditional Chinese medicine have been widely studied and gradually become effective auxiliary means for clinical cancer tumors. Galangin is the active ingredient of traditional Chinese medicine Galangin. Research has found that Galangin has certain anti-tumor activity, which can protect the body from carcinogenic factors and inhibit tumor invasion and migration. Recent studies have shown that galangin can activate the PI3K/Akt pathway to prevent cell death caused by caspase cascade reactions, thereby inhibiting the proliferation, invasion, and migration of liver cancer cells, inducing cancer cell apoptosis, and indirectly regulating cell proliferation and apoptosis by acting on MDM2/p53, ultimately inhibiting malignant proliferation of tumor cells. But whether it can inhibit the progress of breast cancer and its specific mechanism are unknown. Therefore, our research purpose is to use galangin to treat breast cancer, and further clarify its molecular mechanism at the nuclear and molecular level, so as to provide strategies for clinical treatment of breast cancer.

Breast cancer is one of the most common female malignant tumors. In recent years, traditional Chinese medicine has made rapid progress in the clinical treatment and basic research of breast cancer, and has gradually become an effective adjuvant therapy for breast cancer patients after surgery. Galangin is extracted from the traditional Chinese medicine Galangin, and one of its main chemical components, flavonoids, is a class of polyphenolic compounds containing 15 carbon atoms. Recent studies have shown that galangin has a wide range of pharmacological activities, including antiviral, anticancer, anti teratogenic, anti mutagenic, antibacterial, and antispasmodic effects. It can induce apoptosis of liver cancer cells by activating the caspase-8/t-Bid mitochondrial pathway, exert anti liver cancer effects, and induce autophagy through the TGF – β receptor/Smad signaling pathway. Our results suggest that galangin may be a new way to treat breast cancer.

PI3K/Akt signaling pathway is widely involved in various cell processes, such as cell proliferation, cell differentiation and apoptosis. It plays a crucial role in the process of cancer cell proliferation and cell cycle, as well as cell invasion, angiogenesis and metastasis, and is closely related to the occurrence and development of breast cancer. Previous studies have reported that the PI3K/AKT signaling cascade can mediate cell survival through Bcl-2 family members or caspase family proteins, and determine cell fate by regulating caspase activation, as well as changes in pro apoptotic and anti apoptotic proteins. Our results indicate that galangin can downregulate Bcl-2 expression, increase Capsase-9 enzymatic activity, activate Caspase-3, and induce apoptosis by activating the Caspase cascade reaction.

PTEN (MMAC1) is located on human chromosome 10q23.3 and encodes a 403 bp PTEN protein. Its PDZ domain in the tail region of the protein plays an important role in regulating PIP3 levels and PI3K dephosphorylation, inhibiting tumor cell anchoring growth, etc. Due to gene deletion or mutation during tumorigenesis, PTEN expression is inhibited in various malignant tumors. Studies have shown that the inactivation of PTEN in a variety of tumor types, including breast cancer, ovarian cancer, gastric cancer and colon cancer, will lead to the over activation of RTK/PI3K/Akt signal, thus driving the occurrence of tumors. As an inhibitor of PIK3/AKT pathway, PTEN can inhibit the growth and invasion of tumor cells by inhibiting the AKT pathway. Our research results show that the expression of AKT in breast cancer cells or tumor tissue samples is higher than that in the control group. Compared with the control group, the expression of AKT is significantly reduced after treatment with galangin. At the same time, galangin can significantly increase the expression of PTEN, thereby regulating the AKT signal pathway to inhibit the proliferation of breast cancer cells and inhibit tumor progression.

P53 is a tumor suppressor gene located on human chromosome 17p13, encoding the 53kD P53 protein. By binding to the opposite sex DNA site in the nucleus, it upregulates the expression of genes related to cell proliferation inhibition and suppresses the promoter of these genes, thereby blocking the cell cycle and inhibiting cell proliferation to exert its anti-cancer effect. Studies have shown that tumor suppressor gene p53 is closely related to breast hyperplasia and the occurrence and development of breast cancer. The expression changes of regulatory cyclin p53 and p21 can promote G2/M phase arrest of breast cancer cells and induce apoptosis. MDM2 is a natural binding partner and inhibitor of p53, involved in the self-regulation cycle of p53, and can act as a ubiquitin ligase to bind to the p53 activation domain and induce p53 degradation. Our results show that galangin can regulate cell cycle arrest and induce apoptosis of breast cancer cells by up regulating the expression of p53 and p21.

In conclusion, our research shows that galangin can significantly inhibit the expression of MDM2 and Bcl-2, enhance the activity of p53 and Caspases, induce the expression of PTEN and lead to the inactivation of AKT, thereby inhibiting the growth, invasion and migration of breast cancer cells, inhibiting the growth of tumors in vivo, and at the same time increasing the anti-cancer activity of trastuzumab, which has the inhibitory effect on the development of breast cancer and the synergistic effect of trastuzumab. Therefore, galangin may become a potential therapeutic drug for breast cancer.