Abstract. Carnosol, an active constituent of rosemary, has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of carnosol remain poorly understood. In the present study, we found that carnosol significantly reduced the viability of human colon cancer (HCT116) cells in a concentration-and time-dependent manner. Treatment of cells with carnosol induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of poly-(ADP-ribose) polymerase (PARP). Incubation with carnosol elevated the expression of Bax and inhibited the levels of Bcl-2 and Bcl-xl. Carnosol induced expression of p53 and inhibited that of murine-double minute-2 (Mdm2). Moreover, carnosol generated reactive oxygen species (ROS), and pretreatment with N-acetyl cysteine abrogated carnosol-induced cleavage of caspase-3 and PARP. The constitutive phosphorylation, the DNA binding and reporter gene activity of signal transducer and activator of transcription-3 (STAT3) was diminished by treatment with carnosol. To further elucidate the molecular mechanisms of STAT3 inactivation, we found that carnosol attenuated the phosphorylation of Janus-activated kinase-2 (Jak2) and Src kinase. Pharmacological inhibition of Jak2 and Src inhibited STAT3 phosphorylation. Furthermore, carnosol attenuated the expression of STAT3 target gene products, such as survivin, cyclin-D1, -D2, and -D3. Taken together, our study provides the first report that carnosol induced apoptosis in HCT116 cells via generation of ROS, induction of p53, activation of caspases and inhibition of STAT3 signaling pathway. IntroductionDespite a declining trend worldwide, colorectal cancer still remains as the third most common cancer among men and the second in women (1,2). More than one million new cases of colorectal cancer are diagnosed every year (3). A wide variety of natural compounds derived from edible plants have been shown to prevent colon carcinogenesis (4). Carnosol, a diterpene present in rosemary (Rosmarinus officinalis), has been reported to prevent the development of intestinal tumors in APC (adenomatous polyposis coli) min+/+ mice (5) and to induce apoptosis in human colon cancer (COLO 205) cells (6). However, the molecular mechanisms underlying the chemopreventive and/or chemotherapeutic effects of carnosol in colon cancer are yet to be fully elucidated. We, therefore, attempted to investigate the effects of carnosol on human colon cancer (HCT116) cells and to elucidate its underlying mechanisms.One of the hallmarks of cancer is the evasion of tumor cells from apoptosis (7). Numerous naturally occurring polyphenols inhibit proliferation and induce apoptosis in various cancer cells (8). Apoptosis is induced by two cellular mechanisms: intrinsic (mitochondria-dependent) and extrinsic (death receptor-mediated) signaling (9). The intrinsic pathway of apoptosis involves the depolarization of mitochondrial membrane, release of cytochrome c, sequential activation of caspase-9, ...
Carnosic acid (CA), the main antioxidant compound of Rosmarinus officinalis L., has been reported to possess anticancer activity. However, the molecular mechanisms underlying the anticancer effects of CA remain poorly understood. Our study revealed that CA treatment significantly reduced the viability of human colon cancer HCT116, SW480, and HT-29 cells. Treatment with CA induced apoptosis, which was associated with the induction of p53 and Bax, inhibition of Mdm2, Bcl-2, and Bcl-xl expression, activation of caspase-9, and -3, and the cleavage of PARP in HCT116 cells. CA inhibited the constitutive phosphorylation, the DNA binding and the reporter gene activity of STAT3 in HCT116 cells by blocking the phosphorylation of upstream JAK2 and Src kinases. Moreover, CA attenuated the expression of STAT3 target gene products, such as survivin, cyclin D1, D2, and D3. In STAT3-overexpressed HCT116 cells, CA inhibited cell viability and the expression of cyclin D1 and survivin. Furthermore, CA treatment induced the generation of ROS in these colon cancer cells. Pretreatment of cells with ROS scavenger N-acetyl cysteine abrogated the inhibitory effect of CA on the JAK2-STAT3/Src-STAT3 signaling and rescued cells from CA-induced apoptosis by blocking the induction of p53 and the cleavage of caspase-3 and PARP in HCT116 cells. However, L-buthionine-sulfoximine, a pharmacological inhibitor of GSH synthesis, increased CA-induced ROS production, thereby potentiating apoptotic effect of CA. In conclusion, our study provides the first report that CA induced apoptosis in HCT116 cells via generation of ROS, induction of p53, activation of caspases, and inhibition of STAT3 signaling pathway. © 2015 Wiley Periodicals, Inc.
Emerging next generation memories, NVRAMs, such as Phase-change RAM (PRAM), Ferroelectric RAM (FRAM), and Magnetic RAM (MRAM) are rapidly becoming promising candidates for large scale main memory because of their high density and low power consumption. Many researchers have attempted to construct a main memory with NVRAMs, in order to make up for the limits of NVRAMs. However, we find that the preexisting page caching algorithms, such as LRU, LIRS, and CLOCK-Pro, are often sub-optimal for NVRAMs due to its DRAM-oriented design including uniform access latency and unlimited endurance. Consequently, the algorithms cannot be directly adapted to the hybrid main memory architecture with PRAM. To mitigate this design limitation, we propose a new page caching algorithm for the hybrid main memory. It is designed to overcome the long latency and low endurance of PRAM. On the basis of the LRU replacement algorithm, we propose a prediction of page access pattern and migration schemes to maintain write-bound access pages to DRAM. The experiment results have convinced us that our page caching algorithm minimizes the number of the write access of PRAM while maintaining the cache hit ratio. The results show that we can reduce the total write access count by a maximum of 52.9% and the consumed energy by 19.9%. Therefore, we can enhance the average page cache performance and reduce the endurance problem in the hybrid main memory.
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