Skip to main content
SpringerLink
Log in

HSK3486 Inhibits Colorectal Cancer Growth by Promoting Oxidative Stress and ATPase Inhibitory Factor 1 Activation

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

HSK3486 (ciprofol), a new candidate drug similar to propofol, exerts sedative and hypnotic effects through gamma-aminobutyric acid type A receptors; however, its potential role in colorectal cancer is currently unknown.

Aims

This study aimed to evaluate the effects of HSK3486 on colorectal cancer cell proliferation.

Methods

Imaging was performed to detect reactive oxygen species and mitochondrial membrane potential. Western blotting was used to determine the expression of target signals. The HSK3486 molecular mechanism was investigated through ATPase inhibitory factor 1 knockdown and xenograft model experiments to assess mitochondrial function in colorectal cancer cells.

Results

Cell Counting Kit-8 and Annexin V/propidium iodide double staining assays showed that HSK3486 inhibited colorectal cancer cell proliferation in a concentration-dependent manner. In addition, HSK3486 treatment increased the expression of B-cell lymphoma-2-associated X, cleaved caspase 3, and cleaved poly (ADP-ribose) polymerase, whereas myeloid cell leukemia-1 and B-cell lymphoma 2 expression decreased. HSK3486 promoted mitochondrial dysfunction by inducing ATPase inhibitor factor 1 expression. Furthermore, HSK3486 promoted oxidative stress, as shown by the increase in reactive oxygen species and lactate dehydrogenase levels, along with a decrease in mitochondrial membrane potential and ATP levels. ATPase inhibitor factor 1 small interfering RNA pretreatment dramatically increased the mitochondrial membrane potential and tumor size in a xenograft model following exposure to HSK3486.

Conclusion

Collectively, our findings revealed that HSK3486 induces oxidative stress, resulting in colorectal cancer cell apoptosis, making it a potential candidate therapeutic strategy for colorectal cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in the published article.

References

  1. Sung H, Ferlay J, Siegel RL et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–249.

    Article  PubMed  Google Scholar 

  2. de Martel C, Georges D, Bray F, Ferlay J, Clifford GM. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob Health. 2020;8:e180–e190.

    Article  PubMed  Google Scholar 

  3. Bergers G, Fendt SM. The metabolism of cancer cells during metastasis. Nat Rev. Cancer. 2021;21:162–180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer cell. 2008;13:472–482.

    Article  CAS  PubMed  Google Scholar 

  5. Bonora M, Patergnani S, Rimessi A et al. ATP synthesis and storage. Purinergic Signal. 2012;8:343–357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. García-Bermúdez J, Cuezva JM. The ATPase Inhibitory Factor 1 (IF1): a master regulator of energy metabolism and of cell survival. Biochim Biophys Acta. 2016;1857:1167–1182.

    Article  PubMed  Google Scholar 

  7. Tomasetig L, Di Pancrazio F, Harris DA, Mavelli I, Lippe G. Dimerization of F0F1ATP synthase from bovine heart is independent from the binding of the inhibitor protein IF1. Biochim Biophys Acta. 2002;1556:133–141.

    Article  CAS  PubMed  Google Scholar 

  8. Chen X, Wu Q, Sun P et al. Propofol disrupts aerobic glycolysis in colorectal cancer cells via inactivation of the NMDAR-CAMKII-ERK pathway. Cell Physiol Biochem. 2018;46:492–504.

    Article  CAS  PubMed  Google Scholar 

  9. Jacob Z, Li H, Makaryus R et al. Metabolomic profiling of children’s brains undergoing general anesthesia with sevoflurane and propofol. Anesthesiology. 2012;117:1062–1071.

    Article  CAS  PubMed  Google Scholar 

  10. Xu Y, Gao G, Sun X, Liu Q, Li C. ATPase inhibitory factor 1 is critical for regulating sevoflurane-induced microglial inflammatory responses and caspase-3 activation. Front Cell Neurosci. 2021;15:770666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ow YP, Green DR, Hao Z, Mak TW. Cytochrome c: functions beyond respiration. Nat Rev Mol Cell Biol. 2008;9:532–542.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang S, Rao S, Yang M et al. Role of mitochondrial pathways in cell apoptosis during He-patic ischemia/reperfusion injury. Int J Mol Sci. 2022;23:2357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang H, Zhao L, Wu J, Hong J, Wang S. Propofol induces ROS-mediated intrinsic apoptosis and migration in triple-negative breast cancer cells. Oncol Lett. 2020;20:810–816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tan SH, Ding HJ, Mei XP et al. Propofol suppressed cell proliferation and enhanced apoptosis of bladder cancer cells by regulating the miR-340/CDK2 signal axis. Acta Histochem. 2021;123:151728.

    Article  CAS  PubMed  Google Scholar 

  15. Su Z, Liu HL, Qi B, Liu Y. Effects of propofol on proliferation and apoptosis of cardia cancer cells via MAPK/ERK signaling pathway. Eur Rev Med Pharmacol Sci. 2020;24:428–433.

    CAS  PubMed  Google Scholar 

  16. Ye LL, Cheng ZG, Cheng XE, Huang YL. Propofol regulates miR-1-3p/IGF1 axis to inhibit the proliferation and accelerates apoptosis of colorectal cancer cells. Toxicol Res. 2021;10:696–705.

    Article  Google Scholar 

  17. Hu C, Ou X, Teng Y et al. Sedation effects produced by a ciprofol initial infusion or bolus dose followed by continuous maintenance infusion in healthy subjects: a phase 1 trial. Adv Ther. 2021;38:5484–5500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bhattacharya D, Gawali VS, Kallay L et al. Therapeutically leveraging GABA(A) receptors in cancer. Exp Biol Med. 2021;246:2128–2135.

    Article  CAS  Google Scholar 

  19. Kleinerman RA, Brinton LA, Hoover R, Fraumeni JF Jr. Diazepam use and progression of breast cancer. Cancer Res. 1984;44:1223–1225.

    CAS  PubMed  Google Scholar 

  20. Chen W, Di Z, Chen Z et al. NBPF4 mitigates progression in colorectal cancer through the regulation of EZH2-associated ETFA. J Cell Mol Med. 2021;25:9038–9050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Maxwell DP, Wang Y, McIntosh L. The alternative oxidase lowers mitochondrial reactive oxygen production in plant cells. Proc Natl Acad Sci USA 1999;96:8271–8276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhu H, Tan Y, Du W et al. Phosphoglycerate mutase 5 exacerbates cardiac ischemia-reperfusion injury through disrupting mitochondrial quality control. Redox Biol. 2021;38:101777.

    Article  CAS  PubMed  Google Scholar 

  23. Nan K, Han Y, Fang Q et al. HMGB1 gene silencing inhibits neuroinflammation via down-regulation of NF-κB signaling in primary hippocampal neurons induced by Aβ(25–35). Int Immunopharmacol. 2019;67:294–301.

    Article  CAS  PubMed  Google Scholar 

  24. Han Y, Chen R, Lin Q et al. Curcumin improves memory deficits by inhibiting HMGB1-RAGE/TLR4-NF-κB signalling pathway in APPswe/PS1dE9 transgenic mice hippocampus. J Cell Mol Med. 2021;25:8947–8956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Trachootham D, Zhou Y, Zhang H et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell. 2006;10:241–252.

    Article  CAS  PubMed  Google Scholar 

  26. Esparza-Moltó PB, Nuevo-Tapioles C, Cuezva JM. Regulation of the H(+)-ATP synthase by IF1: a role in mitohormesis. Cell Mol Life Sci. 2017;74:2151–2166.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020;5:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Su Z, Hou XK, Wen QP. Propofol induces apoptosis of epithelial ovarian cancer cells by upregulation of microRNA let-7i expression. Eur J Gynaecol Oncol. 2014;35:688–691.

    CAS  PubMed  Google Scholar 

  29. Zhang J, Wu GQ, Zhang Y, Feng ZY, Zhu SM. Propofol induces apoptosis of hepatocellular carcinoma cells by upregulation of microRNA-199a. Cell Biol Int. 2013;37:227–232.

    Article  CAS  PubMed  Google Scholar 

  30. Yu B, Gao W, Zhou H et al. Propofol induces apoptosis of breast cancer cells by downregulation of miR-24 signal pathway. Cancer Biomark. 2018;21:513–519.

    Article  CAS  PubMed  Google Scholar 

  31. Desagher S, Martinou JC. Mitochondria as the central control point of apoptosis. Trends Cell Biol. 2000;10:369–377.

    Article  CAS  PubMed  Google Scholar 

  32. Kang FC, Chen YC, Wang SC, So EC, Huang BM. Propofol induces apoptosis by activating caspases and the MAPK pathways, and inhibiting the Akt pathway in TM3 mouse Leydig stem/progenitor cells. Int J Mol Med. 2020;46:439–448.

    CAS  PubMed  Google Scholar 

  33. Kopeina GS, Prokhorova EA, Lavrik IN, Zhivotovsky B. Alterations in the nucleocytoplasmic transport in apoptosis: caspases lead the way. Cell Prolif. 2018;51:e12467.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Chen BZ, Yin XY, Jiang LH et al. The efficacy and safety of ciprofol use for the induction of general anesthesia in patients undergoing gynecological surgery: a prospective randomized controlled study. BMC Anesthesiol. 2022;22:245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu Y, Yu X, Zhu D et al. Safety and efficacy of ciprofol vs. propofol for sedation in intensive care unit patients with mechanical ventilation: a multi-center, open label, randomized, phase 2 trial. Chin Med J. 2022;135:1043–1051.

    Article  CAS  PubMed  Google Scholar 

  36. Zhu Q, Luo Z, Wang X et al. Efficacy and safety of ciprofol versus propofol for the induction of anesthesia in adult patients: a multicenter phase 2a clinical trial. Int J Clin Pharm. 2023;45:473–482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liao J, Li M, Huang C et al. Pharmacodynamics and pharmacokinetics of HSK3486, a novel 2,6-disubstituted phenol derivative as a general anesthetic. Front Pharmacol. 2022;13:830791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.

    Article  CAS  PubMed  Google Scholar 

  39. Muravchick S, Levy RJ. Clinical implications of mitochondrial dysfunction. Anesthesiology. 2006;105:819–837.

    Article  CAS  PubMed  Google Scholar 

  40. Seo EH, Piao L, Park HJ et al. Impact of general anaesthesia on endoplasmic reticulum stress: propofol vs. isoflurane. Int J Med Sci. 2019;16:1287–1294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lisowska B, Szymańska M, Nowacka E, Olszewska M. Anesthesiology and the cytokine network. Postępy Hig Med Dośw. 2013;67:761–769.

    Article  Google Scholar 

  42. Qin J, Li Y, Wang K. Propofol induces impairment of mitochondrial biogenesis through inhibiting the expression of peroxisome proliferator-activated receptor-γ coactivator-1α. J Cell Biochem. 2019;120:18288–18297.

    Article  CAS  PubMed  Google Scholar 

  43. Zou J, Zhang Y, Sun J et al. Deoxyelephantopin induces reactive oxygen species-mediated apoptosis and autophagy in human osteosarcoma cells. Cell Physiol Biochem. 2017;42:1812–1821.

    Article  CAS  PubMed  Google Scholar 

  44. Gallo M, Sapio L, Spina A et al. Lactic dehydrogenase and cancer: an overview. Front Biosci. 2015;20:1234–1249.

    Article  CAS  Google Scholar 

  45. Franke RP, Fuhrmann R, Mrowietz C et al. Reduced diagnostic value of lactate dehydrogenase (LDH) in the presence of radiographic contrast media. Clin Hemorheol Microcirc. 2010;45:123–130.

    Article  CAS  PubMed  Google Scholar 

  46. Chen WW, Birsoy K, Mihaylova MM et al. Inhibition of ATPIF1 ameliorates severe mitochondrial respiratory chain dysfunction in mammalian cells. Cell Rep. 2014;7:27–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Prieto J, Seo AY, León M et al. MYC induces a hybrid energetics program early in cell reprogramming. Stem Cell Rep. 2018;11:1479–1492.

    Article  CAS  Google Scholar 

  48. Matsuyama S, Xu Q, Velours J, Reed JC. The Mitochondrial F0F1-ATPase proton pump is required for function of the proapoptotic protein Bax in yeast and mammalian cells. Mol Cell. 1998;1:327–336.

    Article  CAS  PubMed  Google Scholar 

  49. Bonora M, Wieckowski MR, Chinopoulos C et al. Molecular mechanisms of cell death: central implication of ATP synthase in mitochondrial permeability transition. Oncogene. 2015;34:1475–1486.

    Article  CAS  PubMed  Google Scholar 

  50. Kwong JQ, Molkentin JD. Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab. 2015;21:206–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wei S, Fukuhara H, Kawada C et al. Silencing of ATPase inhibitory factor 1 inhibits cell growth via cell cycle arrest in bladder cancer. Pathobiology. 2015;82:224–232.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang C, Min L, Liu J et al. Integrated analysis identified an intestinal-like and a diffuse-like gene sets that predict gastric cancer outcome. Tumour Biol. 2016;37:16317–16335.

    Article  CAS  Google Scholar 

  53. Giorgio V, Burchell V, Schiavone M et al. Ca(2+) binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition. EMBO Rep. 2017;18:1065–1076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chidambaran V, Costandi A, D’Mello A. Propofol: a review of its role in pediatric anesthesia and sedation. CNS Drugs. 2015;29:543–563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sahinovic MM, Struys M, Absalom AR. Clinical pharmacokinetics and pharmacodynamics of propofol. Clin Pharmacokinet. 2018;57:1539–1558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Teng Y, Ou M, Wang X et al. Efficacy and safety of ciprofol for the sedation/anesthesia in patients undergoing colonoscopy: phase IIa and IIb multi-center clinical trials. Eur J Pharm Sci. 2021;164:105904.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the National Key Research and Development Program of China (No. 2020YFC2008400), the National Natural Science Foundation of China (No. 82072213, 81873948), the Clinical Research Plan of SHDC (No. SHDC2020CR1005A, SHDC2020CR4064), Shanghai Leading Talent (No. 2019-112), the Shanghai Municipal 2021 Science and Technology Innovation Action Plan (No. 21JC1401400). The authors would like to acknowledge the support of the Intelligent Medical Service Project of Zhongshan Hospital (No. 2020ZHZS25, Shanghai, China).

Author information

Author notes

  1. Ke Nan, Ziwen Zhong, and Ying Yue have contributed equally to this work.

  2. This study combined clinical and basic research. The effect of HSK3486 on colorectal cancer patient was observed and the scientific questions were raised by MD. Minli Sun and Dr. Changhong Miao together. They sought cooperation from Dr. Jie Zhang, who mainly works in the Key Laboratory of Perioperative Stress and Protection. Additional, MD. Sun provided constructive supervision, Dr. Miao provided effective financial support, and Dr. Zhang provided basic technical support for experimental work. The three authors provided constructive advice and revisions during the development of our manuscript.

Authors and Affiliations

  1. Department of Anesthesiology, Zhongshan Hospital, Fudan University, No.180 Feng-Lin Road, Shanghai, 200032, China

    Ke Nan, Ziwen Zhong, Ying Yue, Wenchang Zhou, Xingfeng Sun, Yang Shen, Mengdi Qu, Zhaoyuan Chen, Jiahui Gu, Caihong Sun, Lihong Lu, Jie Zhang, Changhong Miao & Minli Sun

  2. Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Ke Nan, Ziwen Zhong, Ying Yue, Wenchang Zhou, Xingfeng Sun, Yang Shen, Mengdi Qu, Zhaoyuan Chen, Jiahui Gu, Caihong Sun, Lihong Lu, Jie Zhang, Changhong Miao & Minli Sun

  3. Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China

    Ke Nan, Ziwen Zhong, Ying Yue, Wenchang Zhou, Xingfeng Sun, Yang Shen, Mengdi Qu, Zhaoyuan Chen, Jiahui Gu, Caihong Sun, Lihong Lu, Jie Zhang, Changhong Miao & Minli Sun

  4. Department of Anesthesiology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200438, China

    Xingfeng Sun

  5. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Xun Sun

  6. Department of Anesthesiology, Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Lihong Lu

Authors
  1. Ke Nan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ziwen Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenchang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xingfeng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yang Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mengdi Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhaoyuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jiahui Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Caihong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lihong Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Changhong Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Minli Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analyses were performed by KN, ZZ and YY. The first draft of the manuscript was written by ZZ and KN, and JZ, CM and MS conceived and supervised the revision of the manuscript. All authors commented on the previous versions of the manuscript and approved the final manuscript.

Corresponding author

Correspondence to Minli Sun.

Ethics declarations

Conflict of interest

The authors have no financial or proprietary interests in any of the materials discussed in this article.

Ethical approval

All experiments were approved by the Animal Ethics Committee of the Institute Ethics Committee of Zhongshan Hospital, Fudan University, and the Use of Laboratory Animals (license: 202011009S).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 2612 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nan, K., Zhong, Z., Yue, Y. et al. HSK3486 Inhibits Colorectal Cancer Growth by Promoting Oxidative Stress and ATPase Inhibitory Factor 1 Activation. Dig Dis Sci 69, 1214–1227 (2024). https://doi.org/10.1007/s10620-023-08213-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-023-08213-8

Keywords

Search

Navigation