Mitochondria-Targeting Drug Oligomycin Blocked P-Glycoprotein Activity and Triggered Apoptosis in Doxorubicin-Resistant HepG2 Cells

Li, Y.C.; Fung, Kwok‐Pui; Kwok, Tsz-Ho; Lee, C.Y.; Suen, Y. K.; Kong, Siu‐Kai

doi:10.1159/000077803

Cited by 37 publications

(35 citation statements)

References 29 publications

(29 reference statements)

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“…Our results showed that treating DRHEp2 with oligomycin A, an Fo-ATPase inhibitor, reduced docetaxel resistance, whereas inhibitors targeting other MRC and an MRC uncoupler did not reverse docetaxel resistance. Several lines of evidence indicate that oligomycin A is a promoter of apoptosis (Wolvetang et al, 1994;Li et al, 2004); however, other reports suggest that oligomycin A has an inhibitory effect on apoptosis (Matsuyama et al, 1998;Santamaria et al, 2006). Our results indicate that oligomycin A promotes docetaxel-induced cell death in DRHEp2 and that docetaxel resistance is linked with Fo-ATPase activity level.…”

Section: Discussionmentioning

confidence: 42%

Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells

et al. 2007

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Docetaxel is one of the most effective chemotherapeutic agents against cancer; nevertheless, some patients develop resistance. Unfortunately, their causes and mechanisms remain unknown. We created docetaxel-resistant DRHEp2 from human laryngeal cancer HEp2 and investigated the roles of mitochondrial DNA (mtDNA) and reactive oxygen species (ROS) on docetaxel resistance. DRHEp2 had greatly increased mtDNA content. Reduction of mtDNA content in DRHEp2 by ethidium bromide treatment reduced the resistance. These results indicate the possible roles of mtDNA-coded enzymes in mitochondrial respiratory chain (MRC) in resistant mechanisms. Oligomycin A, an Fo-ATPase inhibitor, eliminated docetaxel resistance in DRHEp2; in contrast, inhibitors of other MRC did not. RNA interference targeted to Fo-ATPase d-subunit restored docetaxelinduced cytotoxicity to DRHEp2. These results indicate the roles of Fo-ATPase for resistant mechanisms. Docetaxel induced ROS generation in HEp2 but not in DRHEp2 and antioxidant pyrrolidine dithiocarbamate eliminated docetaxel-induced cytotoxicity, suggesting roles of ROS in docetaxel-induced cell death. Furthermore, inhibition of Fo-ATPase by Oligomycin A induced docetaxel-mediated ROS generation in DRHEp2. Taken together, DRHEp2 acquired docetaxel resistance through increasing Fo-ATPase, which led to diminish docetaxelinduced ROS generation and subsequently inhibited cell death. In conclusion, mtDNA plays an important role in developing docetaxel resistance through the reduction of ROS generation by regulating Fo-ATPase.

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Section: Discussionmentioning

confidence: 42%

Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells

et al. 2007

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“…Oligomycin has been shown to induce apoptosis, but the mechanism of the induction has not been fully elucidated (27). We found that oligomycin enhanced the cytotoxic effect of 425.3PE by affecting the ATP pool and thereby promoting cell death.…”

Section: Discussionmentioning

confidence: 77%

AMP-activated protein kinase protects against anti–epidermal growth factor receptor-Pseudomonas exotoxin A immunotoxin-induced MA11 breast cancer cell death

Andersson

Juell

et al. 2006

Molecular Cancer Therapeutics

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We have shown previously that our 425.3PE immunotoxin inhibits protein synthesis and induces apoptosis in human breast cancer cells. In attempts to further elucidate the intracellular pathways implicated in its cellular effects, we found that the immunotoxin induced an initial stress response, which rapidly caused an imbalance in the cellular energy status with an increase in reactive oxygen species. The AMP-activated protein kinase (AMPK), a sensor of increased cellular AMP/ATP ratio, was activated by 425.3PE. An immunotoxin-induced activation of c-Jun NH 2 -terminal kinase (JNK) preceded and overlapped caspase-mediated cleavage of the A-subunit of AMPK in a time-and dose-dependent manner. The JNK activation occurred already at a dose level too low to induce any detectable changes in the apoptotic machinery or protein synthesis. In contrast, cycloheximide, even at a concentration causing a 90% inhibition of protein synthesis, did neither affect the ATP level nor activate JNK and AMPK. Pretreatment of the cells with the specific AMPK inhibitor compound C and JNK inhibitor SP600125 blocked activation of AMPK and JNK, respectively, and subsequently sensitized the cells to 425.3PE-induced cell death. Whereas the antioxidant N -acetyl-L-cysteine blocked the generation of reactive oxygen species and activation of JNK and AMPK, it did not block immunotoxin-induced apoptosis. Together, the results show that 425.3PE induces several parallel signaling events, observed initially as an early activation of survival pathways, protecting the cells against the toxic effects of the immunotoxin, followed by subsequent apoptosis induction and protein synthesis inhibition. Conceivably, therapeutic manipulation of the signaling intermediates AMPK and JNK might provide a means to maximize the anticancer effects of the 425.3 immunotoxin. [Mol Cancer Ther 2006;5(4):1050 -9]

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“…1 These effects of 1 are of particular importance for the interference with ATP-dependent outward transport and the reversal of drug-resistant phenotypes in bacterial and mammalian cells. 2,3 Furthermore, growing interest in the mechanisms of energy disbalance in disease, to the most part (but not limited to) of cancer, opened the way to the application of 1 as a potent cytotoxic agent. Design of new compounds based on 1 scaffold is of interest, as F 0 F 1 ATP synthase inhibitors are drug candidates for the treatment of bacterial infections and cancer.…”

Section: Introductionmentioning

confidence: 99%

A novel acyclic oligomycin A derivative formed via retro-aldol rearrangement of oligomycin A

et al. 2012

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The antibiotic oligomycin A in the presence of K 2 CO 3 and n-Bu 4 NHSO 4 in chloroform in phase-transfer conditions afforded a novel derivative through the initial retro-aldol fragmentation of the 8,9 bond, followed by further transformation of the intermediate aldehyde. NMR, MS and quantum chemical calculations showed that the novel compound is the acyclic oligomycin A derivative, in which the 8,9 carbon bond is disrupted and two polyfunctional branches are connected with spiroketal moiety in positions C-23 and C-25. The tri-O-acetyl derivative of the novel derivative was prepared. The acyclic oligomycin A derivative retained the ability to induce apoptosis in tumor cells at low micromolar concentrations, whereas its antimicrobial potencies decreased substantially. The derivative virtually lost the inhibitory activity against F 0 F 1 ATP synthasecontaining proteoliposomes, strongly suggesting the existence of the target(s) beyond F 0 F 1 ATP synthase that is important for the antitumor potency of oligomycin A. INTRODUCTIONThe macrolide antibiotic oligomycin A (1) has long been considered a valuable experimental tool for studies of energy metabolism. The major pharmacological activity of 1 is the suppression of oxidative phosphorylation and a decrease of intracellular ATP content due to interaction with the oligomycin-sensitivity-conferring protein component of F 0 F 1 ATP synthase. 1 These effects of 1 are of particular importance for the interference with ATP-dependent outward transport and the reversal of drug-resistant phenotypes in bacterial and mammalian cells. 2,3 Furthermore, growing interest in the mechanisms of energy disbalance in disease, to the most part (but not limited to) of cancer, opened the way to the application of 1 as a potent cytotoxic agent. Design of new compounds based on 1 scaffold is of interest, as F 0 F 1 ATP synthase inhibitors are drug candidates for the treatment of bacterial infections and cancer. 4 Recently, we reported the modifications at the C 7 carbonyl group and the C 2 ¼ C 3 double bond of the antibiotic. 5 Search for rather selective methods of modifications of 1 prompted us to study the behavior of the molecule in the conditions of phase-transfer reactions.

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Mitochondria-Targeting Drug Oligomycin Blocked P-Glycoprotein Activity and Triggered Apoptosis in Doxorubicin-Resistant HepG2 Cells

Cited by 37 publications

References 29 publications

Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells

Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells

AMP-activated protein kinase protects against anti–epidermal growth factor receptor-Pseudomonas exotoxin A immunotoxin-induced MA11 breast cancer cell death

A novel acyclic oligomycin A derivative formed via retro-aldol rearrangement of oligomycin A

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