Hydroxychloroquine based chemical drug for combination therapy with 5-Fu for inhibiting the pathway of Akt/mTOR in autophagy process on colon cancer

Abstract

Abstract: In order to improve the effect of hydroxychloroquine (HCQ) on the selectivity in anti-tumour therapy, the α-linolenic acid conjugated hydroxychloroquine (AHQ) was designed, which was aiming to enhance anti-tumor effect. Basing on the in vitro data of AHQ, we chose colon cancer as the model disease. Herein, we assumed the combined therapy with 5-fluorouracil(5-Fu), which was the corner-stone on the treatment of colon cancer. After the successful synthesis, aqueous solubility, stability of ester bond and in vivo acute toxicity analysis of AHQ, the in vivo bio-distribution of AHQ in the tumour bearing mice model was constructed to verify the increased selectivity in the tumour tissue. The AHQ was demonstrated better tumour selectivity in the HT-29 bearing mice model than HCQ. The synergism effect and best proportion between AHQ and 5-Fu against HT-29 and HCT116 cell lines were 1:1 and 1:8, respectively. The combined group could enhance HT-29 cell apoptosis significantly via arresting the cell cycle in the G0/G1 phase comparing with both AHQ and 5-Fu, while it improved the HCT116 cell apoptosis significantly via arresting the cell cycle in the S phase compared to AHQ. Basing on the prominent consequence in the HT-29 cell line, we naturally chose HT-29 xenograft mouse model to continue the study. The combination group showed excellent effect on suppressing tumour growth by up-regulating the expression of LC3-Ⅱ and P62, and inhibiting the pathway of Akt/mTOR in autophagy process.

Supplementary files

Article information

Article type
Paper
Submitted
22 Jan 2021
Accepted
01 May 2021
First published
03 May 2021

J. Mater. Chem. B, 2021, Accepted Manuscript

Hydroxychloroquine based chemical drug for combination therapy with 5-Fu for inhibiting the pathway of Akt/mTOR in autophagy process on colon cancer

Z. Liao, Y. chen, L. han, D. yu, T. shi, Z. liu and H. Xiao, J. Mater. Chem. B, 2021, Accepted Manuscript , DOI: 10.1039/D1TB00135C

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