Abstract
Lung cancer is the leading cause of cancer deaths in the world, with a five-year survival rate of less than 30%. Clinically effective chemotherapeutic treatments at the initial stage may eventually face the dilemma of no drug being effective due to drug resistance; therefore, finding new effective drugs for lung cancer treatment is a necessary and important issue. Compounds capable of further increasing the oxidative stress of cancer cells are considered to have anticancer potential because they possessed the ability to induce apoptosis. This study mainly investigated the effects of BA6 (heteronemin), the marine sponge sesterterpene, on lung cancer cell apoptosis, via modulation of mitochondrial reactive oxygen species (mtROS) and oxidative phosphorylation (OXPHOS). BA6 has cellular cytotoxic activities against a variety of cancer cell lines, but it has no effect on nontumor cells. The BA6-treated lung cancer cells show a significant increase in both cellular ROS and mtROS, which in turn caused the loss of mitochondrial membrane potential (MMP). The increase of oxidative stress in lung cancer cells treated with BA6 was accompanied by a decrease in the expression of antioxidant enzymes Cu/Zn SOD, MnSOD, and catalase. In addition, OXPHOS performed in the mitochondria and glycolysis in the cytoplasm were inhibited, which subsequently reduced downstream ATP production. Pretreatment with mitochondria-targeted antioxidant MitoTEMPO reduced BA6-induced apoptosis through the mitochondria-dependent apoptotic pathway, which was accompanied by increased cell viability, decreased mtROS, enhanced MMP, and suppressed expression of cleaved caspase-3 and caspase-9 proteins. In conclusion, the results of this study clarify the mechanism of BA6-induced apoptosis in lung cancer cells via the mitochondrial apoptotic pathway, suggesting that it is a potentially innovative alternative to the treatment of human lung cancer.
Highlights
Lung cancer is the most common type of cancer diagnosed in the world and is the leading cause of death of most American cancer patients
Nonmitochondrial respiration-extracellular acidification rate (ECAR) value was decreased to 87 3 ± 4 3 mpH/min/1 × 105 cells (1 μM BA6) and 21 7 ± 2 2 mpH/min/1 × 105 cells (10 μM BA6), respectively, as compared to the control 101 9 ± 4 3 mpH/min/1 × 105 cells (Figure 1(h)). These results suggest that the basal respiration, adenosine 5′-triphosphate (ATP) production, maximal respiration, spare capacity, and ECAR were significantly inhibited after BA6 treatment in A549 cells, while the proton leak remained unaffected
This study demonstrates that the cytotoxic effect of BA6 in lung cancer cells is due to the damage of mitochondrial outer membrane permeabilization (MOMP) via the mitochondria-mediated apoptotic pathway and the release of cytochrome C from the mitochondria
Summary
Lung cancer is the most common type of cancer diagnosed in the world and is the leading cause of death of most American cancer patients. There will be about 234,000 new lung cancer patients in the United States in 2018 and about 154,000 patients will die of lung cancer [1]. In Taiwan, lung cancer is the leading cause of cancer deaths, with a 5-year survival rate of less than 30% [2]. Even though the cost of treating lung cancer in the United States is as high as USD 10.3 billion per year, it cannot reduce the abovementioned high mortality rate [3]. Regardless of whether the targeted drug can be used, the patient will eventually face the difficulty of no available drug and will die; the development of new drugs for lung cancer treatment remains an urgent issue
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