Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells

Guoli Li; Sining Fang; Xiao Shao; Yejia Li; Qingchao Tong; Beibei Kong; Lifen Chen; Yanzhong Wang; Jun Yang; Haitao Yu; Xinyou Xie; Jun Zhang

doi:10.3390/biom11091295

Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells

Biomolecules. 2021 Aug 31;11(9):1295. doi: 10.3390/biom11091295.

Authors

Guoli Li^{1

2}, Sining Fang^{1

2}, Xiao Shao^{1

2}, Yejia Li^{1

2}, Qingchao Tong^{1

2}, Beibei Kong^{1

2}, Lifen Chen^{1

2}, Yanzhong Wang^{1

2}, Jun Yang^{1

2}, Haitao Yu^{1

2}, Xinyou Xie^{1

2}, Jun Zhang^{1

2}

Affiliations

¹ Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
² Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou 310016, China.

Abstract

Nicotinamide N-methyltransferase (NNMT) plays multiple roles in improving the aggressiveness of colorectal cancer (CRC) and enhancing resistance to 5-Fluorouracil (5-FU), making it an attractive therapeutic target. Curcumin (Cur) is a promising natural compound, exhibiting multiple antitumor effects and potentiating the effect of 5-FU. The aim of the present study is to explore the effect of Cur on attenuating NNMT-induced resistance to 5-FU in CRC. A panel of CRC cell lines with different NNMT expressions are used to characterize the effect of Cur. Herein, it is observed that Cur can depress the expression of NNMT and p-STAT3 in CRC cells. Furthermore, Cur can induce inhibition of cell proliferation, G2/M phase cell cycle arrest, and reactive oxygen species (ROS) generation, especially in high-NNMT-expression CRC cell lines. Cur can also re-sensitize high-NNMT-expression CRC cells to 5-FU both in vitro and in vivo. In summary, it is proposed that Cur can reverse NNMT-induced cell proliferation and 5-FU resistance through ROS generation and cell cycle arrest. Given that Cur has long been used, we suppose that Cur is a promising anticancer drug candidate with minimal side effects for human CRC therapy and can attenuate NNMT-induced resistance to 5-FU.

Keywords: cell cycle arrest; chemoresistance; colorectal cancer; curcumin; nicotinamide N-methyltransferase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Cell Cycle Checkpoints* / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Colorectal Neoplasms / enzymology*
Colorectal Neoplasms / pathology*
Curcumin / pharmacology*
Down-Regulation / drug effects
Drug Synergism
Fluorouracil / pharmacology*
Humans
Inhibitory Concentration 50
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Nicotinamide N-Methyltransferase / metabolism*
Phosphorylation / drug effects
Reactive Oxygen Species / metabolism*
STAT3 Transcription Factor / metabolism
Xenograft Model Antitumor Assays

Substances

Reactive Oxygen Species
STAT3 Transcription Factor
Nicotinamide N-Methyltransferase
Curcumin
Fluorouracil