Novel substituted 1,4-anthracenediones with antitumor activity directly induce permeability transition in isolated mitochondria

  • Authors:
    • Elisabeth M. Perchellet
    • Yang Wang
    • Kaiyan Lou
    • Huiping Zhao
    • Srinivas K. Battina
    • Duy H. Hua
    • Jean-Pierre H. Perchellet
  • View Affiliations

  • Published online on: November 1, 2007     https://doi.org/10.3892/ijo.31.5.1231
  • Pages: 1231-1241
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Abstract

Synthetic analogs of 1,4-anthraquinone (AQ code number), which block nucleoside transport, decrease DNA, RNA and protein syntheses, trigger cytochrome c release without caspase activation, induce apoptotic DNA fragmentation and inhibit the proliferation of wild-type and multidrug resistant tumor cells in the nM range in vitro, rapidly cause the collapse of mitochondrial transmembrane potential in cell and cell-free systems. Because mitochondrial permeability transition (MPT) requires more than depolarization to occur, antitumor AQs were tested for their ability to directly trigger specific markers of MPT in isolated mitochondria. In contrast to a spectrum of conventional anticancer drugs that are inactive, various AQs interact with isolated mitochondria in a concentration- and time-dependent manner to rapidly cause large amplitude swelling and Ca2+ release in relation with their effectiveness against L1210, HL-60 and LL/2 tumor cells in vitro. Indeed, the lead antitumor AQ8, AQ9 and AQ17 are also the most effective inducers of MPT in isolated mitochondria, whereas all AQ derivatives devoid of anti-proliferative activity also fail to trigger mitochondrial swelling and Ca2+ release. Moreover, the ability of 4 µM AQ17 to maximally induce mitochondrial swelling and Ca2+ release within 15 min is similar to that of classic MPT-inducing agents, such as 5 µg/ml alamethicin, 200 µM atractyloside, 5 µM phenylarsine oxide, 100 µM arsenic trioxide and a 100 µM Ca2+ overload. Interestingly, AQ17 requires a priming concentration of 20 µM Ca2+ to trigger mitochondrial swelling and Ca2+ release and these 0.1 µM ruthenium red-sensitive MPT events are abolished by 1 µM cyclosporin A, 2 mM ADP and 20 µM bongkrekic acid, which block components of the permeability transition pore (PTP), and also inhibited by 50-100 µM of various ubiquinones, which interact with the quinone binding site of the PTP and raise the Ca2+ load required for PTP opening. Hence, antitumor AQs that target isolated mitochondria and trigger MPT might directly interact with components of the PTP to induce conformational changes that increase its Ca2+ sensitivity and transition from the closed to the open state.

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November 2007
Volume 31 Issue 5

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

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APA
Perchellet, E.M., Wang, Y., Lou, K., Zhao, H., Battina, S.K., Hua, D.H., & Perchellet, J.H. (2007). Novel substituted 1,4-anthracenediones with antitumor activity directly induce permeability transition in isolated mitochondria. International Journal of Oncology, 31, 1231-1241. https://doi.org/10.3892/ijo.31.5.1231
MLA
Perchellet, E. M., Wang, Y., Lou, K., Zhao, H., Battina, S. K., Hua, D. H., Perchellet, J. H."Novel substituted 1,4-anthracenediones with antitumor activity directly induce permeability transition in isolated mitochondria". International Journal of Oncology 31.5 (2007): 1231-1241.
Chicago
Perchellet, E. M., Wang, Y., Lou, K., Zhao, H., Battina, S. K., Hua, D. H., Perchellet, J. H."Novel substituted 1,4-anthracenediones with antitumor activity directly induce permeability transition in isolated mitochondria". International Journal of Oncology 31, no. 5 (2007): 1231-1241. https://doi.org/10.3892/ijo.31.5.1231