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Cancer Cell International
Published in: Cancer Cell International 1/2023

Open Access 01-12-2023 | Statins | Research

Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy

Authors: Masanobu Tsubaki, Tomoya Takeda, Takuya Matsuda, Kana Kishimoto, Honoka Takefuji, Yuzuki Taniwaki, Misa Ueda, Tadafumi Hoshida, Kazufumi Tanabe, Shozo Nishida

Published in: Cancer Cell International | Issue 1/2023

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Abstract

Background

KRAS mutations are fraught with the progression of colorectal cancer and resistance to chemotherapy. There are pathways such as extracellular regulated protein kinase 1/2 (ERK1/2) and Akt downstream and farnesylation and geranylgeranylation upstream that are activated upon mutated KRAS. Previous studies have shown that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are effective to treat KRAS mutated colorectal cancer cells. Increased doses of oxaliplatin (L-OHP), a well-known alkylating chemotherapeutic drug, causes side effects such as peripheral neuropathy due to ERK1/2 activation in spinal cords. Hence, we examined the combinatorial therapeutic efficacy of statins and L-OHP to reduce colorectal cancer cell growth and abrogate neuropathy in mice.

Methods

Cell survival and confirmed apoptosis was assessed using WST-8 assay and Annexin V detection kit. Detection of phosphorylated and total proteins was analyzed the western blotting. Combined effect of simvastatin and L-OHP was examined the allograft mouse model and L-OHP-induced neuropathy was assessed using cold plate and von Frey filament test.

Results

In this study, we examined the effect of combining statins with L-OHP on induction of cell death in colorectal cancer cell lines and improvement of L-OHP-induced neuropathy in vivo. We demonstrated that combined administration with statins and L-OHP significantly induced apoptosis and elevated the sensitivity of KRAS-mutated colorectal cancer cells to L-OHP. In addition, simvastatin suppressed KRAS prenylation, thereby enhancing antitumor effect of L-OHP through downregulation of survivin, XIAP, Bcl-xL, and Bcl-2, and upregulation of p53 and PUMA via inhibition of nuclear factor of κB (NF-κB) and Akt activation, and induction of c-Jun N-terminal kinase (JNK) activation in KRAS-mutated colorectal cancer cells. Moreover, simvastatin enhanced the antitumor effects of L-OHP and suppressed L-OHP-induced neuropathy via ERK1/2 activation in vivo.

Conclusion

Therefore, statins may be therapeutically useful as adjuvants to L-OHP in KRAS-mutated colorectal cancer and may also be useful in the treatment of L-OHP-induced neuropathy.
Appendix
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Metadata
Title
Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy
Authors
Masanobu Tsubaki
Tomoya Takeda
Takuya Matsuda
Kana Kishimoto
Honoka Takefuji
Yuzuki Taniwaki
Misa Ueda
Tadafumi Hoshida
Kazufumi Tanabe
Shozo Nishida
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2023
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-023-02884-z

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