Protocatechuic acid (PCA), present in many fruits and vegetables, exhibited various biological activities. Here, we provided evidence that it could be developed as a potential chemotherapeutic agent against human ovarian cancer. We found that PCA treatment significantly reduced the cell viability and colony formation of OVCAR-3, SKOV-3, and A2780 cells. OVCAR-3 cells were selected as a test model system for investigating molecular mechanism. PCA treatment induced cell cycle arrest in G 2 /M phase, the activation of poly (ADP-ribose) polymerase (PARP) and caspase-3, the upregulation of Bax and downregulation of Bcl-2 in OVCAR-3 cells.We also observed that PCA treatment significantly caused upregulation of autophagy-related protein LC3-II and induced GFP-LC3 puncta formation. Furthermore, cotreatment with PCA and autophagy inhibitor attenuated the cytotoxicity induced by PCA in OVCAR-3 cells. Moreover, our results showed that PCA increased the intracellular levels of glutathione and decreased intracellular reactive oxygen species that might be related to the inhibition effect of PCA on OVCAR-3 cells. Our data revealed that PCA could modulate apoptosis and autophagy, suggesting the potential of PCA for chemoprevention and chemotherapy of ovarian cancer.
In
the current study, nine amide alkaloids, including two new dimeric
amides and a new natural product, were identified from Piper nigrum. Among them, seven compounds sensitized
paclitaxel-resistant cervical cancer cells HeLa/PTX to paclitaxel.
Piperine was a major component obtained from Piper
nigrum, and its sensitization mechanism was investigated.
Combination treatment enhanced cell apoptosis, which was mediated
by downregulation of phospho-Akt and Mcl-1. Piperine (50 μM)
combined with paclitaxel (200 nM) downregulated Mcl-1 protein expression
with a decrease of 35.9 ± 9.5% (P < 0.05).
Moreover, overexpression of Mcl-1 attenuated the inhibitory effect
of this combination. Furthermore, combination treatments of six dimeric
amide alkaloids and paclitaxel all downregulated Mcl-1 protein expression
with a decrease ranging from 23.5 ± 9.7% to 41.7 ± 7.2%
(P < 0.05). We reveal, for the first time, that
dimeric amide alkaloids from plants possess a remarkable sensitization
effect on cancer cells to paclitaxel.
Ovarian cancer is one of leading causes of cancer death in gynecological tumor. Isoalantolactone (IL), present in several medicinal plants, exhibits various biological activities, and its mechanism underlying anti-ovarian cancer activity needs to be further investigated. Here, we find that IL inhibits the proliferation of SKOV-3 and OVCAR-3 cells by causing G2/M phase arrest and inducing apoptosis. Moreover, IL decreases intracellular glutathione (GSH) level, and induces reactive oxygen species (ROS) generation in SKOV-3 cells. Furthermore, IL induces inactivation of Akt which is required for the cytotoxicity of IL. In addition, overexpression of Akt attenuates the IL-induced growth inhibition and ROS generation. GSH supplementation moderately increases the expression of phospho-Akt. Further investigation reveals that pretreatment with L-buthionine-sulfoximine (a GSH biosynthesis inhibitor) restores the Akt-mediated attenuation of growth inhibition induced by IL. Moreover, co-treatment with IL and wortmannin (an Akt pathway inhibitor) increases the growth inhibition attenuated by pretreatment with N-acetyl-L-cysteine (a precursor for GSH biosynthesis). These results indicate that inactivation of Akt and downregulation of GSH level induced by IL are related to each other. In conclusion, combined targeting Akt and GSH is an effective strategy for cancer therapy and IL can be a promising anticancer agent for further exploration.
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