Research articles
ScienceAsia 50 (2024):ID 2024111 1-7 |doi:
10.2306/scienceasia1513-1874.2024.111
Lenalidomide suppresses VEGF-dependent angiogenesis and
cholangiocarcinoma growth in an in vivo mouse model
Kulthida Vaeteewoottacharna,b,c,*, Ryusho Kariyac,d, Saowaluk Saisomboona,c, Natnicha Paungpana,c, Sukanya Luanga,b, Nonthaphol Piyawattanamathab,e, Amnat Kitkhuandeeb,e, Seiji Okadac,*
ABSTRACT: Cholangiocarcinoma (CCA) is an aggressive cancer of the bile duct and is a major health concern in
Thailand. Owing to its heterogeneous nature and clustering of patients in limited resource areas, advancements
in treatment options are limited. Our group previously identified that CCA cells derived from Thai patients could
release high levels of vascular endothelial growth factor (VEGF). Although these cells responded well to the antiVEGF therapy bevacizumab, the induction of hypoxia-inducible factor 1 alpha (HIF1?) was a potential concern.
Therefore, lenalidomide with potent anti-VEGF and anti-HIF1? activities was selected to test anti-CCA activity. The
effects of lenalidomide were investigated both in vitro and in vivo. Tumor volume, tumor weight, and CD31-
immunohistochemistry staining were used to determine tumor growth and angiogenesis. The direct anti-proliferative
effects of lenalidomide were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and
colony-forming assays. The cytokines in the conditioned media (CM) of untreated and lenalidomide-treated cells were
measured using a cytokine array. VEGF in the CM of cells was confirmed by enzyme-linked immunosorbent assay. The
anti-CCA effects of lenalidomide were demonstrated in vivo, as evidenced by the reduced tumor volumes, tumor weights,
and peritumoral and intratumoral vascularization. Decreased CD31-positive areas in tumors from the lenalidomidetreated group confirmed its antiangiogenic effects. Although lenalidomide directly inhibited VEGF production in CCA
cells, it had no direct effect on CCA cell proliferation. The findings suggested that the anti-CCA effect of lenalidomide is
VEGF-dependent; moreover, the safety of lenalidomide warrants further investigation. Ultimately, this study proposed
lenalidomide as a potential treatment option for CCA.
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| a |
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 Thailand |
| b |
Center of Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 Thailand |
| c |
Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection and Graduate School of Medical
Sciences, Kumamoto University, Kumamoto 860-0811 Japan |
| d |
Laboratory of Molecular Cellular Biology, School of Pharmaceutical Sciences, Kobe Gakuin University,
Kobe 650-8586 Japan |
| e |
Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 Thailand |
* Corresponding author, E-mail: kulthidava@kku.ac.th, okadas@kumamoto-u.ac.jp
Received 23 May 2024, Accepted 20 Sep 2024
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