The antioxidant, aged garlic extract, exerts cytotoxic effects on wild-type and multidrug-resistant human cancer cells by altering mitochondrial permeability

  • Authors:
    • Shinji Ohkubo
    • Lisa Dalla Via
    • Silvia Grancara
    • Yuta Kanamori
    • Aída Nelly García-Argáez
    • Gianluca Canettieri
    • Paolo Arcari
    • Antonio Toninello
    • Enzo Agostinelli
  • View Affiliations

  • Published online on: June 22, 2018     https://doi.org/10.3892/ijo.2018.4452
  • Pages: 1257-1268
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Abstract

Aged garlic extract (AGE) has been shown to possess therapeutic properties in cancer; however its mechanisms of action are unclear. In this study, we demonstrate by MTT assay that AGE exerts an anti-proliferative effect on a panel of both sensitive and multidrug-resistant (MDR) human cancer cell lines and enhances the effects of hyperthermia (42˚C) on M14 melanoma cells. The evaluation of the mitochondrial activity in whole cancer cells treated with AGE, performed by cytofluorimetric analysis in the presence of the lipophilic cationic fluorochrome JC-1, revealed the occurrence of dose-dependent mitochondrial membrane depolarization. Membrane potential was measured by the TPP+ selective electrode. In order to shed light on its mechanisms of action, the effects of AGE on isolated rat liver mitochondria were also examined. In this regard, AGE induced a mitochondrial membrane hyperpolarization of approximately 15 mV through a mechanism that was similar to that observed with the ionophores, nigericin or salinomycin, by activating an exchange between endogenous K+ with exogenous H+. The prolonged incubation of the mitochondria with AGE induced depolarization and matrix swelling, indicative of mitochondrial permeability transition induction that, however, occurs through a different mechanism from the well-known one. In particular, the transition pore opening induced by AGE was due to the rearrangement of the mitochondrial membranes following the increased activity of the K+/H+ exchanger. On the whole, the findings of this study indicate that AGE exerts cytotoxic effects on cancer cells by altering mitochondrial permeability. In particular, AGE in the mitochondria activates K+/H+ exchanger, causes oxidative stress and induces mitochondrial permeability transition (MPT).
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September-2018
Volume 53 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Ohkubo S, Dalla Via L, Grancara S, Kanamori Y, García-Argáez AN, Canettieri G, Arcari P, Toninello A and Agostinelli E: The antioxidant, aged garlic extract, exerts cytotoxic effects on wild-type and multidrug-resistant human cancer cells by altering mitochondrial permeability. Int J Oncol 53: 1257-1268, 2018.
APA
Ohkubo, S., Dalla Via, L., Grancara, S., Kanamori, Y., García-Argáez, A.N., Canettieri, G. ... Agostinelli, E. (2018). The antioxidant, aged garlic extract, exerts cytotoxic effects on wild-type and multidrug-resistant human cancer cells by altering mitochondrial permeability. International Journal of Oncology, 53, 1257-1268. https://doi.org/10.3892/ijo.2018.4452
MLA
Ohkubo, S., Dalla Via, L., Grancara, S., Kanamori, Y., García-Argáez, A. N., Canettieri, G., Arcari, P., Toninello, A., Agostinelli, E."The antioxidant, aged garlic extract, exerts cytotoxic effects on wild-type and multidrug-resistant human cancer cells by altering mitochondrial permeability". International Journal of Oncology 53.3 (2018): 1257-1268.
Chicago
Ohkubo, S., Dalla Via, L., Grancara, S., Kanamori, Y., García-Argáez, A. N., Canettieri, G., Arcari, P., Toninello, A., Agostinelli, E."The antioxidant, aged garlic extract, exerts cytotoxic effects on wild-type and multidrug-resistant human cancer cells by altering mitochondrial permeability". International Journal of Oncology 53, no. 3 (2018): 1257-1268. https://doi.org/10.3892/ijo.2018.4452