OSW-1 induces apoptosis and cyto-protective autophagy, and synergizes with chemotherapy on triple negative breast cancer metastasis.

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.

• Authors: Mengling Wu, Qianrui Huang, Mengya Liao, Xuyi Wu, Huizhi Xi, Hongbo Ma, Shanrui Li, Yiwen Zhang, Yong Xia
• Journal: Cellular oncology (Dordrecht) (Cell Oncol (Dordr)) Vol. 45 Issue 6 Pg. 1255-1275 (Dec 2022) ISSN: 2211-3436 [Electronic] Netherlands
• PMID: 36155886 (Publication Type: Journal Article)
• Copyright: © 2022. Springer Nature Switzerland AG.

Chemical References

• OSW 1
• Phosphatidylinositol 3-Kinases
• Doxorubicin
• Docetaxel

Topics

• Humans
• Mice
• Animals
• Triple Negative Breast Neoplasms (pathology)
• Phosphatidylinositol 3-Kinases
• Cell Line, Tumor
• Cell Proliferation
• Apoptosis
• Autophagy
• Doxorubicin (pharmacology, therapeutic use)
• Docetaxel (pharmacology, therapeutic use)