An ex vivo organ culture screening model revealed that low temperature conditions prevent side effects of anticancer drugs

Tian Tian,Ami Funada,Kanako Miyazaki,Tsutomu Iwamoto,Yao Fu,Kanji Mizuta,Yuta Chiba,Yuna Ando,Ichiro Takahashi,Aya Yamada,Satoshi Fukumoto,Keita Funada,Seiji Nakamura,Tomomi Yuta,Xue Han,Jumpei Kawahara,Keigo Yoshizaki

doi:10.1038/s41598-022-06945-7

Abstract

Development of chemotherapy has led to a high survival rate of cancer patients; however, the severe side effects of anticancer drugs, including organ hypoplasia, persist. To assume the side effect of anticancer drugs, we established a new ex vivo screening model and described a method for suppressing side effects. Cyclophosphamide (CPA) is a commonly used anticancer drug and causes severe side effects in developing organs with intensive proliferation, including the teeth and hair. Using the organ culture model, we found that treatment with CPA disturbed the growth of tooth germs by inducing DNA damage, apoptosis and suppressing cellular proliferation and differentiation. Furthermore, low temperature suppressed CPA-mediated inhibition of organ development. Our ex vivo and in vitro analysis revealed that low temperature impeded Rb phosphorylation and caused cell cycle arrest at the G1 phase during CPA treatment. This can prevent the CPA-mediated cell damage of DNA replication caused by the cross-linking reaction of CPA. Our findings suggest that the side effects of anticancer drugs on organ development can be avoided by maintaining the internal environment under low temperature.

Highlights

Development of chemotherapy has led to a high survival rate of cancer patients; the severe side effects of anticancer drugs, including organ hypoplasia, persist
We demonstrated that organ damage by CPA treatment could be suppressed under cold temperature
CPA inhibited the growth of tooth germ, and the severity of CPA-mediated damage on tooth germ varied depending on the developmental stage of tooth germ when CPA was administered

Summary

Introduction

Development of chemotherapy has led to a high survival rate of cancer patients; the severe side effects of anticancer drugs, including organ hypoplasia, persist. Cyclophosphamide (CPA) is a commonly used anticancer drug and causes severe side effects in developing organs with intensive proliferation, including the teeth and hair. Using the organ culture model, we found that treatment with CPA disturbed the growth of tooth germs by inducing DNA damage, apoptosis and suppressing cellular proliferation and differentiation. Our ex vivo and in vitro analysis revealed that low temperature impeded Rb phosphorylation and caused cell cycle arrest at the G1 phase during CPA treatment. Organs which show intensive proliferation in the formative period are easy targets for cytotoxic drugs For this reason, teeth, salivary grands, hair, and taste buds undergo damage as side-effects of chemotherapy. These phenomena are consistent with the process, timing, and sequence of tooth d evelopment[23]

Methods

Results

Conclusion