Novel dual inhibitor for targeting PIM1 and FGFR1 kinases inhibits colorectal cancer growth in vitro and patient-derived xenografts in vivo.
10.1016/j.apsb.2022.07.005
- Author:
Fanxiang YIN
1
;
Ran ZHAO
1
;
Dhilli Rao GORJA
2
;
Xiaorong FU
1
;
Ning LU
1
;
Hai HUANG
2
;
Beibei XU
1
;
Hanyong CHEN
3
;
Jung-Hyun SHIM
4
;
Kangdong LIU
1
;
Zhi LI
5
;
Kyle Vaughn LASTER
2
;
Zigang DONG
1
;
Mee-Hyun LEE
1
Author Information
1. Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
2. China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China.
3. The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
4. Department of Biomedicine, Health & Life Convergencen Science, BK21 Four, College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea.
5. Department of General Surgery, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450008, China.
- Publication Type:Journal Article
- Keywords:
Colorectal cancer;
FGFR1;
HCI-48;
Kinase activity;
PIM1;
Patient-derived xenograft model;
Small molecule compound of chalcone;
Targeted therapy
- From:
Acta Pharmaceutica Sinica B
2022;12(11):4122-4137
- CountryChina
- Language:English
-
Abstract:
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world. The pro-viral integration site for Moloney murine leukemia virus 1 (PIM1) is a proto-oncogene and belongs to the serine/threonine kinase family, which are involved in cell proliferation, migration, and apoptosis. Fibroblast growth factor receptor 1 (FGFR1) is a tyrosine kinase that has been implicated in cell proliferation, differentiation and migration. Small molecule HCI-48 is a derivative of chalcone, a class of compounds known to possess anti-tumor, anti-inflammatory and antibacterial effects. However, the underlying mechanism of chalcones against colorectal cancer remains unclear. This study reports that HCI-48 mainly targets PIM1 and FGFR1 kinases, thereby eliciting antitumor effects on colorectal cancer growth in vitro and in vivo. HCI-48 inhibited the activity of both PIM1 and FGFR1 kinases in an ATP-dependent manner, as revealed by computational docking models. Cell-based assays showed that HCI-48 inhibited cell proliferation in CRC cells (HCT-15, DLD1, HCT-116 and SW620), and induced cell cycle arrest in the G2/M phase through modulation of cyclin A2. HCI-48 also induced cellular apoptosis, as evidenced by an increase in the expression of apoptosis biomarkers such as cleaved PARP, cleaved caspase 3 and cleaved caspase 7. Moreover, HCI-48 attenuated the activation of downstream components of the PIM1 and FGFR1 signaling pathways. Using patient-derived xenograft (PDX) murine tumor models, we found that treatment with HCI-48 diminished the PDX tumor growth of implanted CRC tissue expressing high protein levels of PIM1 and FGFR1. This study suggests that the inhibitory effect of HCI-48 on colorectal tumor growth is mainly mediated through the dual-targeting of PIM1 and FGFR1 kinases. This work provides a theoretical basis for the future application of HCI-48 in the treatment of clinical CRC.
