Combined treatment with sorafenib and betulinic acid inhibits cell proliferation by causing a G2 cell cycle arrest in human pancreatic cancer cells

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers worldwide due to a late diagnosis and poor response to available treatments. It’s important to identify treatment strategies that will enhance the efficacy and reduce the toxicity of currently used therapeutic.

Material and methods: In this study, PDAC cell lines: AsPC-1, BxPC-3 and Capan-1, were treated with sorafenib and betulinic acid alone and in combination. We examined the effect of combined treatments on viability (MTS test), proliferation (trypan blue staining) and apoptosis (Annexin V staining), cell cycle arrest (PI staining), alterations in signaling pathways (Western blotting) and colony-forming ability.

Results and discussion: The combination of sorafenib with betulinic acid inhibits viability and cells number of PADAC cells without apoptosis. The anti-proliferative effect through be induced by G2 cell cycle arrest, which were strongly associated with increased expression of p21, decreased expression of c-Myc and cyclin D1. Additionally, decreased proliferation can be also connected with inhibition of P13K/Akt and MAPK signaling pathway. Significant, combination treatment reduced colony-forming ability of PDAC cells, as compared to both compounds alone.

Conclusion: Collectively, we showed that combination therapy with low concentrations of sorafenib and betulinic acid had the capacity to inhibit proliferation and abolish clonogenic activity in some PDAC cell lines.