Isocudraxanthone K Induces Growth Inhibition and Apoptosis in Oral Cancer Cells via Hypoxia Inducible Factor-1α

Abstract

Isocudraxanthone K (IK) is a novel, natural compound from a methanol extract of the root bark of Cudrania tricuspidata. It has not been shown previously that IK possessed antitumor activity. We investigated the antitumor effects and molecular mechanism of IK and related signal transduction pathway(s) in oral squamous cell carcinoma cells (OSCCCs). The MTT assay revealed that IK had an antiproliferative effect on OSCCCs, in a dose- and time-dependent manner. IK induced apoptosis in OSCCCs, as identified by a cell-cycle analysis, annexin V-FITC and propidium iodide staining, and the nuclear morphology in cell death. IK caused time-dependent phosphorylation of Akt, p38, and ERK (extracellular signal-regulated kinase). In addition, IK increased the cytosolic to nuclear translocation of nuclear factor-κB (NF-κB) p65 and the degradation and phosphorylation of IκB-α in HN4 and HN12 cells. Furthermore, IK treatment downregulated hypoxia-inducible factor 1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF). Cobalt chloride (CoCl2), a HIF-1α activator, attenuated the IK-induced growth-inhibiting and apoptosis-inducing effects, and blocked IK-induced expression of apoptosis regulatory proteins, such as Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, and cytochrome c. Collectively, these data provide the first evidence of antiproliferative and apoptosis-inducing effects of IK as a HIF-1α inhibitor and suggest it may be a drug candidate for chemotherapy against oral cancer.

Cobalt chloride affects the death of SH-SY5Y cells induced by inhibition of ubiquitin proteasome system. Role of heat shock protein 70 and caspase 3

“…For example, fast apoptotic death of primary hippocampal and cortical neurones induced by ABT-737 that was shown to induce Bax/Bak-dependent mitochondrial apoptosis (Vogler et al 2009) was not prevented but was significantly delayed by application of the broad spectrum caspase inhibitor zVADfmk (Young et al 2010). In accord with our results, CoCl 2 at concentrations 100 and 200 μmol/l blocked isocudraxanthone-induced apoptosis and activa-tion of caspase 3 (Shin et al 2014). Concentration of CoCl 2 seems to be critical with respect to the impact of CoCl 2 on the exposed cells.…”

“…Finally, other mechanisms activated by CoCl 2 , e.g. modulation of expression of Bcl2 family proteins (Shin et al 2014), could to contribute to protective effects of CoCl 2 .…”

Induction of mitochondria-mediated apoptosis and suppression of tumor growth in zebrafish xenograft model by cyclic dipeptides identified from Exiguobacterium acetylicum

“…Further, we observed the expression levels of apoptotic (Cytc, Casp-3 and Bid) and anti-apoptotic (Bcl-2) markers were up-and down-regulated in HT-29 cells in response to DKPs treatments. A possible explanation for the significant up-regulation of Casp-3 in DKPs treated cells, in this study may be activated by an initiator caspase such as Casp-9 36,37 . However, all DKPs induces apoptosis by directly activating Casp-3 or by cleaving Bid (BH3 interacting-domain death agonist), resulting in mitochondrial dysfunction and subsequent release of Cytc and activation of Casp-9 and Casp-3 17 .…”

Functional significance of CD105-positive cells in papillary renal cell carcinoma

“…The ability to create colonies was measured with the use of the semi-soft agar method [29]. Cells after passage were collected as described above, and 2,000 cells were seeded into a 96-well plate according to the Stem Cell Colony Formation Assay (Cell Biolabs, San Diego, CA, USA) protocol.…”