Marcell Baranyi1 ,Tamás Garay1,2, Dominika Rittler1, Eszter Molnár1, István Jalsovszky3, Luca Hegedűs4, József Tóvári5, József Tímár1, Balázs Hegedűs1,4
1 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
2 HAS Postdoctoral Fellowship Program Hungarian Academy of Sciences, Budapest, Hungary
3 Faculty of Science, Institute of Chemistry, Department of Organic Chemistry, Eötvös Loránd University, Budapest, Hungary
4 Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, Germany
5 Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary
Bisphosphonates are clinically approved drugs for treatment of bone metastases and showed direct antitumor activity via prenylation-inhibition in preclinical experiments. However, the high affinity to bone material of currently used bisphosphonates limits their application elsewhere. Recently, lipophilic bisphosphonates were developed to overcome this obstacle and showed promising results on models of lung cancer.
Aim of this study was to compare efficacy of the clinically approved zoledronate and a novel lipophilic bisphosphonate (BPH1222) using in vitro and in vivo models of colorectal cancer.
Seven colorectal cancer cell lines were involved in this study. Impact of zoledronate and BPH1222 on proliferation and on cell cycle distribution was investigated using 2D cell cultures via clonogenic assay and DNA content based image cytometry, respectively. Inhibitory potential of the two drugs on spheroid growth was also measured to determine their activity in 3D environment. Finally, we validated our in vitro results using subcutaneous xenograft tumors.
Dose dependent inhibition of proliferation was observed by clonogenic assay in all cell lines for both drugs. In certain cell lines BPH1222 while in others zoledronate was more effective. Sensitivity showed no correlation with mutations of RAS/RAF/MAPK pathway. Both drugs showed a similar impact on the cell-cycle distribution. Importantly, in contrast to two dimensional assays, BPH1222 was significantly more effective in 3D environment in spheroid growth inhibition. Similarly, subcutaneous tumor growth was also more potently inhibited by the lipophilic bisphosphonate.
Our study demonstrates anti-cancer activity of bisphosphonates using in vitro and in vivo models of colorectal cancer. Results of 3D spheroid cultures and in vivo experiment suggest that lipophilic BPH1222 can exert a higher anti-tumor activity in 3D environment than clinically approved zoledronate. Accordingly, further investigations of lipophilic bisphosphonates are warranted in order to explore the clinical utility of bisphosphonates beyond bone associated pathologies.
Doctoral School: Pathological Sciences
Program: Experimental Oncology
Supervisor: József Tímár