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The inhibition of autophagy by spautin boosts the anticancer activity of fingolimod in multidrug-resistant hepatocellular carcinoma
Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Pharm, Sharjah, U Arab Emirates..
Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Pharm, Sharjah, U Arab Emirates..
Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Med, Sharjah, U Arab Emirates..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm 32512, Egypt..ORCID iD: 0000-0002-2519-6690
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2022 (English)In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 304, article id 120699Article in journal (Refereed) Published
Abstract [en]

The contribution of autophagy to drug resistance has been studied in several cancers. However, there is no clear evidence about the role of autophagy in the resistance to chemotherapy in cancers, such as hepatocellular carcinoma (HCC). HCC is characterized by a poor prognosis and limited therapeutic options. Moreover, the emergence of multidrug-resistance (MDR) hinders successful treatment. Therefore, understanding how autophagy is regulated in resistant HCC is essential for sensitizing this malignancy to chemotherapy. This work demonstrated that basal and induced autophagy differ between parental and resistant Hep3B cells. In optimum growth conditions, the basal level of autophagy was low in resistant Hep3B (Hep3B-R) cells compared to the wild-type Hep3B (Hep3B-P) cells. However, in metabolic or therapeutic stress conditions, the rate of autophagy flux was much faster in the resistant cells. The work also confirmed the pro-survival function of autophagy in HCC. Besides, it demonstrated that the autophagy inhibitor, spautin, acted synergistically with fingolimod (FTY720) to promote cell death. The combination treatment resulted in superior reactive oxygen species (ROS) production and significant induction of apoptosis. In addition, spautin potentiated the effect of FTY720 against cell survival pathways like the Akt and ERK. Interestingly, the results indicated that Hep3B-R cells were more sensitive to autophagy inhibition than their parental counterparts. Collectively, this work revealed that combining spautin with chemotherapeutic agents that induce cytoprotective autophagy such as FTY720 is a promising approach to overcome MDR in HCC.

Place, publisher, year, edition, pages
Elsevier BV Elsevier, 2022. Vol. 304, article id 120699
Keywords [en]
Autophagy, Multidrug-resistance, Liver cancer, Apoptosis, Spautin, Fingolimod
National Category
Cell Biology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-480364DOI: 10.1016/j.lfs.2022.120699ISI: 000814755000009PubMedID: 35690108OAI: oai:DiVA.org:uu-480364DiVA, id: diva2:1682586
Available from: 2022-07-11 Created: 2022-07-11 Last updated: 2024-01-15Bibliographically approved

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El-Seedi, Hesham

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