Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Nov 23:13:1014854.
doi: 10.3389/fphar.2022.1014854. eCollection 2022.

Discovery of highly potent and selective 7-ethyl-10-hydroxycamptothecin-glucose conjugates as potential anti-colorectal cancer agents

Chao Yang  1   2   3 , An-Jie Xia  1 , Cheng-Hao Du  4 , Ming-Xing Hu  1 , You-Ling Gong  5 , Rong Tian  6 , Xin Jiang  7 , Yong-Mei Xie  1
Affiliations

Discovery of highly potent and selective 7-ethyl-10-hydroxycamptothecin-glucose conjugates as potential anti-colorectal cancer agents

Chao Yang et al. Front Pharmacol. .

Abstract

7-Ethyl-10-hydroxycamptothecin (SN38), a highly potent metabolite of irinotecan, has an anticancer efficacy 100-1000 folds more than irinotecan in vitro. However, the clinical application of SN38 has been limited due to the very narrow therapeutic window and poor water solubility. Herein, we report the SN38-glucose conjugates (Glu-SN38) that can target cancer cells due to their selective uptake via glucose transporters, which are overexpressed in most cancers. The in vitro antiproliferative activities against human cancer cell lines and normal cells of Glu-SN38 were investigated. One of the conjugates named 5b showed high potency and selectivity against human colorectal cancer cell line HCT116. Furthermore, 5b remarkably inhibited the growth of HCT116 in vivo. These results suggested that 5b could be a promising drug candidate for treating colorectal cancer.

Keywords: 7-ethyl-10-hydroxycamptothecin; anticancer; colorectal cancer; glucose conjugates; warburg effect.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

SCHEME 1
SCHEME 1
Synthesis of Glu-SN38. Reagents and conditions: (A) (BOC)2O, pyridine, DCM, 12 h; (B) propargyl alcohol, triphosgene, DMAP, DCM, 2 h; (C) glucose azides (β-D-Glucopyranosyl azide, 2-azidoethyl β-D-glucopyranoside or 2-(2-azidoethoxy) ethyl β-D-glucopyranoside), CuSO4 .5H2O, sodium ascorbate, THF/H2O, 12 h; (D) TFA, DCM, 2 h.
FIGURE 1
FIGURE 1
(A) Uptake of Glu-SN38 via glucose transporters using fluorescent probe 2-NBDG as competitor in HCT116 cells. (B) Effect of incubation time on IC50 values. (C) Effect of D-glucose on IC50 values. (D) Changes in IC50 values of 5b and irinotecan in cancer and normal cells.
FIGURE 2
FIGURE 2
5b induced HCT116 cells apoptosis (A)The apoptosis rate of HCT116 cells treated by 5b and irinotecan. (B) Statistic results of apoptosis assays. Data are expressed as mean ± S.D. from three independent experiments (***p < 0.001).
FIGURE 3
FIGURE 3
5b inhibited HCT116 cells migration. (A) Wound healing assay. (B) Statistic results of wound healing assay (***p < 0.001).
FIGURE 4
FIGURE 4
(A) Stability of compound 5b in PBS (pH 5.5 and pH 7.4) and plasma. (B) The body weight of the mice during the treatment. (C) Tumor growth of HCT116 model inhibited by 5b (**p < 0.01; ***p < 0.001). (D) Represented weight of tumors from mice of different groups, respectively. Data were mean ± S.D. (n = 5, *p < 0.05). (E) Representative photographs of subcutaneous tumors in the HCT116 model.
FIGURE 5
FIGURE 5
Evaluation of side effects of 5b in mice. (A) Blood chemistry analysis. (B) Blood routine analysis. (C) HE staining of the sections of the liver, kidney, spleen, lung, and heart from the mice in four groups after treatment.
FIGURE 6
FIGURE 6
Expression of Ki-67 and CC3 in HCT116 tumor tissues.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Abigerges D., Chabot G. G., Armand J. P., Hérait P., Gouyette A., Gandia D. (1995). Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J. Clin. Oncol. 13 (1), 210–221. 10.1200/jco.1995.13.1.210 - DOI - PubMed
    1. Aiyangar A., Rajput P., Shah B. (2010). Mycophenolate induced diarrhoea. J. Assoc. Physicians India 58, 192–194. - PubMed
    1. Bray F., Ferlay J., Soerjomataram I., Siegel R. L., Torre L. A., Jemal A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca. Cancer J. Clin. 68 (6), 394–424. 10.3322/caac.21492 - DOI - PubMed
    1. Calvaresi E. C., Hergenrother P. J. (2013). Glucose conjugation for the specific targeting and treatment of cancer. Chem. Sci. 4 (6), 2319–2333. 10.1039/C3SC22205E - DOI - PMC - PubMed
    1. Cao J., Cui S., Li S., Du C., Tian J., Wan S., et al. (2013). Targeted cancer therapy with a 2-deoxyglucose-based adriamycin complex. Cancer Res. 73 (4), 1362–1373. 10.1158/0008-5472.can-12-2072 - DOI - PubMed

LinkOut - more resources