Next Generation Lipophilic Bisphosphonate Shows Antitumor Effect in Colorectal Cancer In Vitro and In Vivo
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ORIGINAL ARTICLE
Next Generation Lipophilic Bisphosphonate Shows Antitumor Effect in Colorectal Cancer In Vitro and In Vivo Marcell Baranyi 1 & Dominika Rittler 1 & Eszter Molnár 1 & Senji Shirasawa 2 & István Jalsovszky 3 & Imre Károly Varga 3 & Luca Hegedűs 4 & Afrodíté Németh 5 & Magdolna Dank 5 & Clemens Aigner 4 & József Tóvári 6 & József Tímár 1 & Balázs Hegedűs 1,4 & Tamás Garay 1,6,7,8 Received: 23 October 2019 / Accepted: 5 December 2019 # Arányi Lajos Foundation 2020
Abstract Bisphosphonates, despite proven antitumor effect in vitro in many tumor types, are currently used only for treatment of osteoporosis and bone metastasis. Colorectal cancer is the third most commonly diagnosed type of cancer and lacks targeted therapy for RAS or RAF mutation carrying cases. A new lipophilic bisphosphonate showed promising results in lung cancer models, but their effect on colorectal cancer cells was not investigated excessively. Antitumor effects and impact on RAS-related signalization of zoledronic acid (ZA) and a lipophilic bisphosphonate (BPH1222) were investigated on 7 human colorectal cancer cell lines in vitro and in vivo. Furthermore, mutant KRAS dependent effect of prenylation inhibition was investigated using isogeneic cell lines. Both bisphosphonates reduced cell viability in vitro in a dose-dependent manner. Both compounds changed cell cycle distribution similarly by increasing the proportion of cells either in the S or in the subG1 phase or both. However, BPH1222 exerted higher inhibitory effect on spheroid growth than ZA. Interestingly, we found profound alterations in phosphorylation level of Erk and S6 proteins upon ZA or BPH1222 treatment. Furthermore, investigation of a mutant KRAS isogeneic model system suggests that the drugs interfere also with the mutant KRAS proteins. In vivo experiments with KRAS mutant xenograft model also revealed growth inhibitory potential of bisphosphonate treatment. Our results show that lipophilic bisphosphonates might extend the therapeutic spectrum of bisphosphonate drugs and could be considered as additional treatment approaches in colorectal cancer. Keywords Lipophilic bisphosphonate . Zoledronic acid . Colorectal cancer . In vitro . In vivo
* Balázs Hegedűs [email protected] Marcell Baranyi [email protected] Dominika Rittler [email protected] Eszter Molnár [email protected] Senji Shirasawa [email protected] István Jalsovszky [email protected] Imre Károly Varga [email protected]
Luca Hegedűs [email protected] Afrodíté Németh [email protected] Magdolna Dank [email protected] Clemens Aigner [email protected] József Tóvári [email protected] József Tímár [email protected] Tamás Garay [email protected] Extended author information available on the last page of the article
M. Baranyi et al.
Background Colorectal cancer is the third most commonly diagnosed type of cancer and the fourth most common cause of cancer-related death worldwi
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