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Antitumor triptycene analogs directly interact with isolated mitochondria to rapidly trigger markers of permeability
Elisabeth M Perchellet1, Yang Wang, Kaiyan Lou
1Anti-Cancer Drug Laboratory, Division of Biology, Ackert Hall, Kansas State University, Manhattan, KS 66506-4901, USA.
Background:
Substituted triptycenes (TT code number), which block nucleoside transport, macromolecule syntheses and DNA topoisomerase activities, induce cytochrome c release and apoptotic DNA fragmentation, inhibit the proliferation of drug-sensitive and -resistant tumor cells in the nM range in vitro and rapidly trigger the collapse of mitochondrial transmembrane potential in cell and cell-free systems. Because mitochondrial permeability transition (MPT) requires more than depolarization, antitumor TTs were tested for their ability to directly trigger specific markers of MPT in isolated mitochondria.
Materials And Methods:
Large amplitude swelling and Ca2+ release were assayed in isolated mitochondria to demonstrate TT-induced MPT.
Results:
Antitumor TTs interact with isolated mitochondria in a concentration- and time-dependent manner to rapidly cause large amplitude swelling and Ca2+ release in relation with their antiproliferative activities in L1210, HL-60 and LL/2 tumor cells in vitro. The ability of 4-10 uM TT15, TT16 and TT24 to maximally induce mitochondrial swelling and Ca2+ release within 20 min is similar to that of classic MPT inducers, such as 5 microg/ml alamethicin, 200 microM atractyloside, 5 microM phenylarsine oxide, 100 microM arsenic trioxide and a 100 microM Ca2+ overload. TT15 requires a priming concentration of 20 microM Ca2+ to trigger mitochondrial swelling and Ca2+ release and these 0.1 microM ruthenium red-sensitive MPT events are abolished by 1 microM cyclosporin A, 2 mM ADP and 20 microM bongkrekic acid, which block components of the permeability transition pore (PTP), and by 50-100 microM of various ubiquinones, which interact with the quinone binding site of the PTP and raise the Ca2+ load required for PTP opening.
Conclusion:
Antitumor TTs that trigger MPT in isolated mitochondria might interact with components of the PTP to boost its Ca2+-sensitive transition from the closed to the open state and might be valuable to develop mitochondriotoxic drugs that directly activate early components of apoptosis.
Insights
Substituted triptycenes (TTs) trigger mitochondrial permeability transition (MPT) by directly opening the permeability transition pore (PTP). This mitochondriotoxic effect correlates with their potent anticancer activity, suggesting new therapeutic strategies.
Area of Science:
- Mitochondrial biology
- Cancer therapeutics
- Molecular pharmacology
Background:
- Substituted triptycenes (TTs) exhibit potent anticancer properties by inhibiting proliferation and inducing apoptosis.
- TTs rapidly collapse mitochondrial transmembrane potential, but the precise mechanism beyond depolarization was unclear.
- Investigating TTs' direct impact on mitochondrial permeability transition (MPT) is crucial for understanding their antitumor effects.
Purpose of the Study:
- To determine if antitumor substituted triptycenes (TTs) directly induce mitochondrial permeability transition (MPT) in isolated mitochondria.
- To elucidate the mechanism by which TTs trigger MPT and its relation to their antiproliferative activity.
Main Methods:
- Assay of large amplitude swelling and Ca2+ release in isolated mitochondria to detect TT-induced MPT.
- Concentration- and time-dependent studies of TT effects on mitochondria.
- Evaluation of MPT markers and inhibition by known permeability transition pore (PTP) blockers.
Main Results:
- Antitumor TTs induced mitochondrial swelling and Ca2+ release in a concentration- and time-dependent manner, correlating with antiproliferative activity.
- The MPT induction by TTs was comparable to established inducers like alamethicin and atractyloside.
- TT-induced MPT events were sensitive to calcium, ruthenium red, cyclosporin A, ADP, bongkrekic acid, and ubiquinones, indicating interaction with the PTP.
Conclusions:
- Antitumor TTs directly trigger MPT in isolated mitochondria, likely by interacting with PTP components.
- TTs may enhance the Ca2+-sensitive transition of the PTP from closed to open states.
- These findings support the development of mitochondriotoxic drugs targeting the PTP for cancer therapy.
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