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Enhancing tetrandrine cytotoxicity in human lung carcinoma A549 cells by suppressing mitochondrial ATP production

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Abstract

ATP depletion induced by inhibiting glycolysis or mitochondrial ATP production has been demonstrated to cause cancer cell death. Whether ATP depletion can enhance the efficacy and potency of anti-cancer effects of herbal compounds is so far unknown. We examined the enhancing effect of ATP depletion on anti-cancer actions of tetrandrine (TET) in human lung carcinoma A549 cells. A 24-h incubation of A549 cells with tetrandrine caused a concentration-dependent cytotoxic effect (LC50 = 66.1 μM). Co-incubation with 20 mM 2-deoxyglucose (2-DG, glycolysis inhibitor) caused only a very slight enhancement of tetrandrine cytotoxicity. By contrast, inhibiting mitochondrial ATP production with oligomycin (10 μM, ATP synthase inhibitor) and FCCP (30 μM, uncoupling agent) (thus, oligo-FCCP) on its own caused only slight cell cytotoxicity but strongly potentiated tetrandrine cytotoxicity (tetrandrine LC50 = 15.6 μM). The stronger enhancing effect of oligo-FCCP than 2-DG on TET toxicity did not result from more severe overall ATP depletion, since both treatments caused a similar ATP level suppression. Neither oligo-FCCP nor 2-DG synergized with tetrandrine in decreasing mitochondrial membrane potential. TET on its own triggered reactive oxygen species (ROS) production, and oligo-FCCP, but not 2-DG, potentiated TET in causing ROS production. Taken together, our results suggest that inhibiting ATP production from mitochondria, but not from glycolysis, appears to be a very effective means in augmenting TET-triggered ROS production and hence toxicity in A549 cells.

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Funding

Macau Science and Technology Development Fund (FUNDO PARA O DESENVOLVIMENTO DAS CIÊNCIAS E DA TECNOLOGIA) for support (Grant number 002/2015/A1) (LWCC). China Medical University, Taiwan, and the Ministry of Science and Technology of Taiwan for providing funding (103-2320-B-039-015-; 104-2320-B-039-030-; 104-2320-B-039-013-; 105-2320-B-039-028-; DMR-106-086; DMR-106-089; DMR-107-083; DMR-108-083) (Y.M.L., K.L.W, and K.S.C.).

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Authors and Affiliations

  1. State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China

    Louis W. C. Chow

  2. UNIMED Medical Institute and Organisation for Oncology and Translational Research, Hong Kong, China

    Louis W. C. Chow

  3. Organisation for Oncology and Translational Research, Hong Kong, China

    Louis W. C. Chow

  4. Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan

    Ka-Shun Cheng & Kar-Lok Wong

  5. Department of Anaesthesiology of Centro Hospitalar conde de Sao Januario, Macao Health Bureau, Macau, SAR, China

    Fai Leong

  6. Laboratory and Clinical Research Institute for Pain, Department of Anaesthesiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    Chi-Wai Cheung & Kar-Lok Wong

  7. Department of Physiology, China Medical University, No.91, Hsueh-Shih Road, Taichung, 40402, Taiwan, Republic of China

    Lian-Ru Shiao & Yuk-Man Leung

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  1. Louis W. C. Chow
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  2. Ka-Shun Cheng
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Contributions

LRS conducted the experiments. LWCC, KSC, FL, and CWC participated in research design and data analysis. LWCC, YML, and KLW wrote the paper. All the authors read and approved the manuscript.

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Correspondence to Yuk-Man Leung or Kar-Lok Wong.

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No humans or animals were used in this study; only cell lines were used in this work and therefore ethical approval is not required.

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Chow, L.W.C., Cheng, KS., Leong, F. et al. Enhancing tetrandrine cytotoxicity in human lung carcinoma A549 cells by suppressing mitochondrial ATP production. Naunyn-Schmiedeberg's Arch Pharmacol 392, 427–436 (2019). https://doi.org/10.1007/s00210-018-01601-2

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  • DOI: https://doi.org/10.1007/s00210-018-01601-2

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