OSW-1 induces apoptosis and cyto-protective autophagy, and synergizes with chemotherapy on triple negative breast cancer metastasis.
Cell Oncol (Dordr)
; 45(6): 1255-1275, 2022 Dec.
Article
em En
| MEDLINE
| ID: mdl-36155886
ABSTRACT
PURPOSE:
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. As yet, chemotherapy with drugs such as doxorubicin is the main treatment strategy. However, drug resistance and dose-dependent toxicities restrict their clinical use. Natural products are major sources of anti-tumor drugs. OSW-1 is a natural compound with strong anti-cancer effects in several types of cancer, but its effects on the efficacy of chemotherapy in TNBC and its underlying mechanism remain unclear.METHODS:
The inhibitory activities of OSW-1 and its combination with several chemotherapy drugs were tested using in vitro assays and in vivo subcutaneous and metastatic mouse TNBC models. The effects of the mono- and combination treatments on TNBC cell viability, apoptosis, autophagy and related signaling pathways were assessed using MTT, flow cytometry, RNA sequencing and immunology-based assays. In addition, the in vivo inhibitory effects of OSW-1 and (combined) chemotherapies were evaluated in subcutaneous and metastatic mouse tumor models.RESULTS:
We found that OSW-1 induces Ca2+-dependent mitochondria-dependent intrinsic apoptosis and cyto-protective autophagy through the PI3K-Akt-mTOR pathway in TNBC cells in vitro. We also found that OSW-1 and doxorubicin exhibited strong synergistic anti-TNBC capabilities both in vivo and in vitro. Combination treatment strongly inhibited spontaneous and experimental lung metastases in 4T1 mouse models. In addition, the combination strategy of OSW-1 + Carboplatin + Docetaxel showed an excellent anti-metastatic effect in vivo.CONCLUSIONS:
Our data revealed the mode of action and molecular mechanism underlying the effect of OSW-1 against TNBC, and provided a useful guidance for improving the sensitivity of TNBC cells to conventional chemotherapeutic drugs, which warrants further investigation.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias de Mama Triplo Negativas
Tipo de estudo:
Guideline
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article