Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models

Abstract

Breast cancer is the most common female cancer with considerable metastatic potential, explaining the need for new candidates that inhibit tumor metastasis. In our study, betulinic acid (BA), a kind of pentacyclic triterpenoid compound derived from birch trees, was evaluated for its anti-metastasis activity in vitro and in vivo. BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion. In addition, BA could inhibit the activation of stat3 and FAK which resulted in a reduction of matrix metalloproteinases (MMPs), and increase of the MMPs inhibitor (TIMP-2) expression. Moreover, in our animal experiment, intraperitoneal administration of 10 mg/kg/day BA suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without obvious side effects. Furthermore, histological and immunohistochemical analyses showed a decrease in MMP-9 positive cells, MMP-2 positive cells and Ki-67 positive cells and an increase in cleaved caspase-3 positive cells upon BA administration. Notably, BA reduced the number of myeloid-derived suppressor cells (MDSCs) in the lungs and tumors. Interestingly, in our caudal vein model, BA also obviously suppressed 4T1 tumor pulmonary metastases. These findings suggested that BA might be a potential agent for inhibiting the growth and metastasis of breast cancer.

Role of STAT3 signaling pathway in breast cancer

“…Niclosamide, that was reported to be a potent STAT3 inhibitor in TNBC cells, was found to overcome the radioresistance in TNBC cells via inhibition of STAT3 and Bcl-2 activation and induction of reactive oxygen species (ROS) [97]. In addition, flubendazole (FLU), a widely used anthelmintic agent, eupalinolide J, a Michaelreaction acceptor extracted from Eupatorium lindleyanum, and betulinic acid are found to inhibit STAT3 activation in breast cancer cells [98][99][100]. As an upstream activator of STAT3, inhibition of JAK2 can undoubtedly suppress STAT3 activation.…”

Betulin and betulinic acid: triterpenoids derivatives with a powerful biological potential

“…The use of xenograft mouse models in subsequent studies led to the conclusion that the survival time of xenograft mice with ovarian cancer treated with BA was much longer than the mice in the control group (Zuco et al 2002). Another study, on mouse models as well, revealed that BA could inhibit breast cancer growth and lung metastasis (Zeng et al 2018). Significantly, subsequent BA studies using xenograft mice proved that it is well absorbed and distributed in the tumour at the highest concentration (Shin et al 1999).…”

Betulin and betulinic acid in cancer research

“…Subsequently, while studying the influence of betulinic acid on ovarian carcinoma xenografts, scientists learned that the survival time of mice treated with betulinic acid was significantly extended compared to control [34]. Of note, a different study also revealed a decreased number of lung metastases in animals with highly malignant and metastatic breast tumours treated with betulinic acid [35].…”