Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics

Abstract

Cambogin, a bioactive polycyclic polyprenylated acylphoroglucinol (PPAP) derived from the Garcinia genus, possesses proapoptotic effect in medulloblastoma and breast cancer cells. We have previously demonstrated that the proapoptotic effect of cambogin is driven by the production of reactive oxygen species (ROS). Here we have shown that the inhibitory effect of cambogin on cell proliferation is associated with the loss of mitochondrial transmembrane potential (ΔΨm) and mitochondrial fragmentation. Cambogin also promotes the mutual complex formation of the membrane-bound subunit p22phox of NADPH oxidase 1 (NOX1), as well as the phosphorylation of the cytosolic subunit p47phox, subsequently enhancing membrane-bound NOX1 activity, which leads to increases in intracellular and mitochondrial levels of O2.- and H2O2. Pharmacological inhibition of NOX1 using apocynin (pan-NOX inhibitor), ML171 (NOX1 inhibitor) or siRNA against NOX1 prevents the increases in O2.- and H2O2 levels and the anti-proliferative effect of cambogin. Antioxidants, including SOD (superoxide dismutase), CAT (catalase) and EUK-8, are also able to restore cell viability in the presence of cambogin. Besides, cambogin increases the dissociation of thioredoxin-1 (Trx1) from ASK1, switching the inactive form of ASK1 to the active kinase, subsequently leads to the phosphorylation of JNK/SAPK, which is abolished upon ML171 treatment. The proapoptotic effect of cambogin in breast cancer cells is also aggravated upon knocking down Trx1 in MCF-7 cells. Taken in conjunction, these data indicate that the anti-proliferative and pro-apoptotic effect of cambogin is mediated via inducing NOX1-dependent ROS production and the dissociation of ASK1 and Trx1.

Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression

“…Cambogin, a naturally-occurring polycyclic polyprenylated acylphloroglucinol, displayed cytostatic and apoptosis-inducing effects in breast cancer cell lines. Increased mitochondrial superoxide as well as cytosolic NADPH oxidase 1 (Nox1)-mediated ROS generation paralleled elevated mitochondrial fission and diminished ∆ Ψ m following cambogin treatment [ 222 ]. The mechanism of action of cambogin may involve the release of ASK1 from inhibition by Trx1.…”

Gold nanoparticles reduce high glucose-induced oxidative-nitrosative stress regulated inflammation and apoptosis via tuberin-mTOR/NF-κB pathways in macrophages

“…3,35 More importantly, cells contain a large number of antioxidants to prevent or repair the damage caused by ROS/RNS, as well as regulate redox-sensitive signaling cascades in diverse cell types during hyperglycemia. 4 37 Similarly, the GPx reduces organic hydroperoxides, while GSH helps in the redox regulation of cellular compartments and offers a defense mechanism against oxidant stress in a thiol-sensitive fashion. 38 Our results show that the activity of antioxidants such as SOD, GPx and GSH decreases in HG condition in macrophages, but the antioxidants level improved with increasing dose of AuNPs.…”

Redox Paradox: A Novel Approach to Therapeutics-Resistant Cancer

“…Inhibition of NOX1 with siRNA in K-ras-transformed normal rat kidney cells resulted in a marked decrease in neovascularization (178). Inhibition of NOX1 by using the natural compound Cambogin in breast cancer decreased cancer metastasis (303). Inhibition of NOX1 with DPI decreased ROS production and resulted in an inhibition of the malignant phenotypes, growth, and invasion (307).…”