Search

In this study, we interrogated the mechanism by which the immunosuppressant FTY720 mediates anticancer effects in oral squamous cell carcinoma (OSCC) cells. FTY720 differentially suppressed the viability of the OSCC cell lines SCC4, SCC25, and SCC2095 with IC 50 values of 6.1, 6.3, and 4.5 μM, respectively. This antiproliferative effect was attributable to the ability of FTY720 to induce caspase-dependent apoptosis. Mechanistic evidence suggests that FTY720-induced apoptosis was associated with its ability to inhibit Akt-NF-κB signaling, to facilitate the proteasomal degradation of the antiapoptotic protein Mcl-1, and to increase reactive oxygen species (ROS) generation. Both overexpression of Mcl-1 and inhibition of ROS partially protected cells from FTY720-induced caspase-9 activation, PARP cleavage and cytotoxicity. In addition, FTY720 induced autophagy in OSCC cells, as manifested by LC3B-II conversion, decreased p62 expression, and accumulation of autophagosomes. Inhibition of autophagy by bafilomycin A1 protected cells from FTY720-induced apoptosis. Together, these findings suggest an intricate interplay between autophagy and apoptosis in mediating the tumor-suppressive effect in OSCC cells, which underlies the translational potential of FTY720 in fostering new therapeutic strategies for OSCC.

The antitumor activity of 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated. TCD suppressed the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values at 72 h of 19 and 23 μM, respectively, via a PPARγ-independent manner. TCD induced cell apoptosis accompanied with pleiotrophic biological modulations including down-regulation of Akt-NF-κB signaling, up-regulation of p38 mitogen-activated protein kinase and p53, increased reactive oxygen species generation, inhibition of histone deacetylases protein expression, and cytoprotective autophagy. Together, these findings provided the translational value of TCD and wild bitter gourd as an antitumor agent for patients with breast cancer.

Secondary metabolites in marine organisms exhibit various pharmacological activities against diseases, such as cancer. In this study, the anti‐proliferative effect of JBIR‐100, a macrolide isolated from Streptomyces sp., was investigated in breast cancer cells. Cell growth was inhibited in response to JBIR‐100 treatment concentration‐ and time‐dependently in both MCF‐7 and MDA‐MB‐231 breast cancer cells. JBIR‐100 caused apoptosis, as verified by caspase activation and the cleavage of PARP. Western blotting revealed that JBIR‐100 modulated the expression of Akt/NF‐κB signaling components and Bcl‐2 family members. Overexpression of Mcl‐1 partially rescued MCF‐7 cells from JBIR‐100‐induced cytotoxicity. In addition, transmission electron microscopy analyses, confocal analysis, and western blot assay indicated that JBIR‐100 inhibited autophagy in MCF‐7 cells. Exposure to the autophagy inhibitor did not synergize JBIR‐100‐induced apoptosis. In summary, our results suggested that JBIR‐100 may be potentially used for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract: 5′ AMP‐activated protein kinase enzyme (AMPK), a master regulator of cellular metabolism, is recognized for its association with various metabolic diseases, inflammation and cancer. In this study, we aimed to investigate the role of compound 59, an AMPK activator, in a panel of oral squamous cell carcinoma (OSCC) cell lines. The antiproliferative effects of compound 59 were assessed by MTT assays, flow cytometry, Western blotting, confocal microscopy and transmission electron microscopy. Relative to OSCC cells, normal human oral keratinocytes were almost insensitive to compound 59 treatment. Compound 59 induced apoptosis as indicated by caspase activation and PARP cleavage. In addition, it inhibited JAK/STAT3 signalling, arrested cells in the G1 phase, increased reactive oxygen species (ROS) generation and promoted autophagy. Interestingly, pre‐treatment with a protein tyrosine phosphatase (PP2A) inhibitor, cantharidin, partially reversed compound 59‐induced down‐regulation of p‐JAK2 and p‐STAT3, thereby suggesting the involvement of a protein tyrosine phosphatase. Together, these findings substantiate the potential of compound 59 for the treatment of OSCC patients. [ABSTRACT FROM AUTHOR]

The antitumour mechanism of alphitolic acid (ALA), an anti-inflammatory triterpene, in oral squamous cell carcinoma (OSCC) cells was investigated. ALA suppressed the proliferation of SCC4 and SCC2095 OSCC cells with IC 50 values of 12 and 15 µM, respectively, via apoptotic induction. Mechanistically, this drug effect on apoptosis was, in part, associated with its ability to block Akt–NF-κB signalling. Moreover, ALA induced autophagy, as evidenced by increased expression of the autophagy biomarkers Beclin 1, Atg7, and LC3B-II, and autophagosome formation. This autophagy induction played a protective role as autophagy inhibitors enhanced cellular susceptibility to ALA-induced apoptosis. Also noteworthy is the involvement of p53 in ALA-mediated cytotoxicity. ALA increased p53 phosphorylation/expression, accompanied by parallel decreases in the expression of the oncogenic E3 ligase MDM2, and shRNA-mediated knockdown of p53 partially rescued ALA-mediated cytotoxicity. Together, these findings suggest the translational value of ALA as an ingredient in functional food/dietary supplement for OSCC prevention. [ABSTRACT FROM AUTHOR]