Cantharidin suppressed breast cancer MDA-MB-231 cell growth and migration by inhibiting MAPK signaling pathway

Abstract

As an active constituent of the beetle Mylabris used in traditional Chinese medicine, cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays a crucial role in cell cycle progression, apoptosis, and cell fate. The role and possible mechanisms exerted by cantharidin in cell growth and metastasis of breast cancer were investigated in this study. Cantharidin was found to inhibit cell viability and clonogenic potential in a time- and dose-dependent manner. Cell cycle analysis revealed that cell percentage in G2/M phase decreased, whereas cells in S and G1 phases progressively accumulated with the increasing doses of cantharidin treatment. In a xenograft model of breast cancer, cantharidin inhibited tumor growth in a dose-dependent manner. Moreover, high doses of cantharidin treatment inhibited cell migration in wound and healing assay and downregulated protein levels of major matrix metalloproteinases (MMP)-2 and MMP-9. MDA-MB-231 cell migration and invasion were dose-dependently inhibited by cantharidin treatment. Interestingly, the members of the mitogen-activated protein kinase (MAPK) signaling family were less phosphorylated as the cantharidin dose increased. Cantharidin was hypothesized to exert its anticancer effect through the MAPK signaling pathway. The data of this study also highlighted the possibility of using PP2A as a therapeutic target for breast cancer treatment.

Cantharidin‐induced LO2 cell autophagy and apoptosis via endoplasmic reticulum stress pathway in vitro

“…Further, it is a highly toxic traditional Chinese medicine (TCM), which is commonly used in the clinical treatment of cancer (Prasad et al, 2009; Wang, 1989), particularly for primary liver cancer. Cantharidin (CTD) is the major component of Mylabris ; it exerts a strong anti‐tumor effect (Puerto Galvis, Vargas Méndez, & Kouznetsov, 2013) by suppressing cell growth and migration, and inducing apoptosis (Chin‐Chuan et al, 2016; Gu, Xu, Zhao, & Gu, 2017; Huh, Kang, Chae, Kyoo, & Kim, 2004). Furthermore, compared with traditional chemotherapeutic drugs, CTD can increase the number of leukocytes and cytokines for improving immune function (Shou et al, 2013; Wang, Li, Xin, & Lv, 2016).…”

Cantharidin Inhibits Anti-Apoptotic Bcl-2 Family Proteins and Induces Apoptosis in Human Osteosarcoma Cell Lines MG-63 and MNNG/HOS via Mitochondria-Dependent Pathway

“…2) By promoting the expression of ROS, and then downregulating Bcl-2 expression, increasing pro-apoptotic Bax expression, and activating the mitochondrial apoptosis pathway [ 38 , 39 ]. 3) By activation of the MAPK and ERK signal transduction pathway [ 40 , 41 ].…”

Anticancer Attributes of Cantharidin: Involved Molecular Mechanisms and Pathways

“…CTD can efficaciously inhibit the growth of both CML K562 and CML resistant cells k562R by downregulating BCR-ABL transcription level [ 52 ]. Moreover, CTD can induce growth inhibition in triple-negative breast cancer cell lines, MDA-MB-231 [ 45 , 53 ] and MDA-MB-468, which is the most difficult breast cancer type to cure due to resistance to the already established breast cancer therapies, i.e., endocrine therapies and HER-2 targeted therapy [ 54 ]. Taken together, these data represents that CTD is a puissant cytotoxic agent that can suppress carcinoma cells growth and proliferation time and dose-dependently.…”

“…CTD also induced G 2 /M phase arrest in osteosarcoma cells with increasing CHK1, phosphorylated p53 and WEE1 expression level, while decreasing CDC25C and CDK1 expression [ 68 ]. Moreover, it was able to induce G 2 /M phase in hepatocellular carcinoma derived stem cells, CD133 + [ 71 ], breast cancerous cells, MDA-MB-231 [ 53 ], colorectal cancerous cells, HCT-116 [ 18 ] and in renal cancerous cells, ACHN and Caki-1 RCC [ 67 ]. Therefore, it is certain that CTD can arrest the cancerous cell cycle by regulating various cell cycle-associated proteins expression levels as summarized in Table 1 ( Figure 4 ).…”