Combination of fruquintinib with venetoclax for the treatment of colorectal cancer
WEI ZHANG1,3,#, WEICHENG WANG1,#, RUI WANG1, XIAO HAN1, LIJUN ZHU1, WENJIE GUO2,*, YANHONG GU1,*
1 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
2 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
3 Department of Oncology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, 225300, China
* Address correspondence to: Yanhong Gu, guyhphd@163.com;
Wenjie Guo, guowj@nju.edu.cn
#
These authors contributed equally to this work
Oncology Research https://doi.org/10.32604/or.2024.050047
Received 25 January 2024; Accepted 17 April 2024; Published online 22 May 2024
Abstract
Background: As a novel blocker of vascular endothelial growth factor receptor (VEGFR), fruquintinib has been
approved for treating colorectal cancer (CRC). However, its dosage and therapeutic efficacy are limited by its widespread
adverse reactions. Venetoclax, recognized as the initial inhibitor of B-cell lymphoma protein 2 (BCL2), has shown
potential in boosting the effectiveness of immunotherapy against CRC. This study investigated the efficacy and
mechanisms of fruquintinib combined with venetoclax in treating CRC.
Methods and Materials: We developed a
colon cancer mouse model with the CT26 cell line to demonstrate fruquintinib and venetoclax’s efficacy against
tumors. Then we employed various techniques to evaluate different aspects of the experimental outcomes.
Immunohistochemistry was used to detect cell proliferation and angiogenesis in tumor tissues. Western blot analysis
was utilized to examine the occurrence of cell apoptosis, and flow cytometry to quantitate immune cells within the
tumor tissues. Moreover, immunofluorescence was employed to measure cytokine levels.
Results: The strongest
inhibition on tumor growth was achieved by the combination of fruquintinib with venetoclax, as opposed to
individual drug use. Venetoclax was found to amplify the impact of fruquintinib, leading to decreased cancer cell
proliferation, increased cancer cell apoptosis, lowered angiogenesis, better vascular structure normalization, and
improved immune cell infiltration.
Conclusion: Our findings indicate that the addition of venetoclax enhances the
impact of fruquintinib on vascular normalization and modulation of the tumor immune microenvironment. Our
study presents the justification for utilizing the fruquintinib and venetoclax combination in treating CRC. Venetoclax
holds promise in being assimilated into anticancer medications for CRC.
Graphical Abstract
Keywords
Colorectal cancer (CRC), B-cell lymphoma protein 2 (BCL2), Venetoclax, Vascular endothelial growth factor receptor (VEGFR), Fruquintinib, Anti-angiogenesis, Immunotherapy
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