Thioridazine combined with carboplatin results in synergistic inhibition of triple negative breast cancer by targeting cancer stem cells.

Cancer stem cells (CSCs) in triple-negative breast cancer (TNBC) are closely related to tumorigenesis and metastasis. Thioridazine (THZ) is a usual phenothiazine antipsychotic drug that can destroy CSCs. We aimed to explore whether THZ could sensitize metastatic TNBC cells, especially the CSCs, to carboplatin (CBP) treatment. Metastatic TNBC cells, 4T1 cells, and tumor-bearing mice were treated with THZ and CBP as monotherapy or combination therapy. MTT, flow cytometry, electron microscopy, immunohistochemistry and western blotting were applied to assess the cell viability, apoptosis, mitochondrial morphology and the relevant protein levels, respectively. Tumor size and lung metastasis under different treatments as well as tumorigenesis of residual tumor cells from each group were monitored. THZ combined with CBP inhibited 4T1 tumor cell proliferation and induced apoptosis by inhibiting the PI3K-AKT-mTOR pathway and activating estrogen receptor stress. THZ also showed strong activity against breast CSCs, THZ combined with CBP significantly destroyed cancer cells, inhibited lung metastasis and relieved the tumor burden; Our data demonstrated that THZ can sensitize TNBC cells to CBP treatment and this combination therapy may provide a bright strategy for TNBC treatment by targeting both cancer cells and CSCs.

[Relationship between the reduction of FHIT expression and the development of cervical carcinoma].

OBJECTIVE: To explore the relationship between reduction of FHIT expression of fragile histidine triad (FHIT) and the development of cervical carcinoma. METHODS: Expression of the FHIT product was detected by immunohistochemistry in 22 normal cervices and 35 cervical intra-epithelial neoplasias (CINs) as well as 60 primary invasive cervical carcinomas. RESULTS: The rates for loss or reduction of expression of FHIT protein in the squamous epithelium of normal cervices, CIN I-II, CIN III and noninvasive carcinoma and invasive cervical carcinoma were 0% (0/22), 20% (4/20), 53.3% (8/15), 81.7% (49/60) respectively (P<0.05). Among the well differentiated, intermediately differentiated and poorly differentiated invasive cervical carcinoma, the rates for loss or reduction of expression of FHIT protein were 60.0% (6/10), 70.0% (14/20), and 96.7% (29/30) respectively (P<0.05). The rate of the impaired FHIT protein expression in the invasive cervical carcinoma with lymph node metastasis (90.9%) was higher than that without lymph node metastasis (79.6%). CONCLUSION: The impaired FHIT protein expression might be a useful indicator in identifying the possibility of the progression of advanced CINs into invasive cervical carcinoma. FHIT protein expression might indicate the clinical characteristic of cervical carcinoma cells and the prognosis of cervical carcinoma.