Novel synergistic antitumor effects of rapamycin with bortezomib on hepatocellular carcinoma cells and orthotopic tumor model

<p>Abstract</p> <p>Background</p> <p>Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the chemotherapy efficacy against HCC is still unsatisfactory. The mammalian target of rapamycin (mTOR) has been emerged as an important cancer therapeutic target. However, HCC cells often resistant to rapamycin because of the paradoxical activation of Akt by rapamycin. In this study, we investigated whether bortezomib could enhance the antitumor effects of rapamycin.</p> <p>Methods</p> <p>The effects of rapamycin and bortezomib on HCC proliferation, apoptosis, migration, and invasiveness <it>in vitro</it> were assessed by CCK-8 analysis, flow cytometry, Hoechst 33342 staining and transwell assays, respectively. Total and phosphorylated protein levels of Akt were detected by Western blotting. The effects of rapamycin and/or bortezomib on the mRNA expression levels of p53, p27, p21 and Bcl-2 family in HCCLM3 cells were evaluated by RT-PCR. The roles of rapamycin and bortezomib on HCC growth and metastasis in xenograft models were evaluated by tumor volumes and fluorescent signals. The effects of rapamycin and bortezomib on cell proliferation and apoptosis <it>in vivo</it> were test by PCNA and TUNEL staining.</p> <p>Results</p> <p>Bortezomib synergized with rapamycin to reduce cell growth, induce apoptosis, and inhibit cell mobility <it>in vitro</it>. Further mechanistic studies showed that bortezomib inhibited rapamycin-induced phosphorylated Akt, which in turn enhanced apoptosis of HCC cell lines. The alteration of the mRNA expression of cell cycle inhibitors p53, p27, p21 and apoptosis associated genes Bcl-2, Bax were also involved in the synergistic antitumor effects of rapamycin and bortezomib. P53 inhibitor PFT-α significantly attenuate the effect of rapamycin and bortezomib on cell apoptosis, which indicated that the pro-apoptotic effect of rapamycin and bortezomib may be p53-dependent. Treatment of HCCLM3-R bearing nude mice with rapamycin and bortezomib significantly enhanced tumor growth inhibition (72.4%), comparing with either rapamycin- (54.7%) or bortezomib-treated mice (22.4%). In addition, the lung metastasis was significantly suppressed in mice received the combination treatment (16.6%). The combination treatment of rapamycin and bortezomib significantly inhibited tumor cell proliferation and tumor angiogenesis <it>in vivo</it>.</p> <p>Conclusion</p> <p>The combination of rapamycin with bortezomib could be a novel and promising therapeutic approach to the treatment of HCC.</p

Understanding credit card payment behavior among college students

College students remain a lucrative target market for credit card companies even after the advent of the Credit Card Act of 2009. Unfortunately, many students are not prepared to use credit responsibly or make payments in a timely manner. Numerous studies reveal risky student credit behaviors, lack of credit knowledge or irresponsible management of credit. However, there remains a need for more information on college students\u27 payment behaviors. This paper aims to explain credit card payment behavior among college students by segmenting college students into payment behavior groupings. Using an online survey, students provided their credit card payment activity and demographic characteristics. The results of this study shed light on different credit card payment behaviors by segmenting college students into four behavioral segments based on useful characteristics. Clear distinctions exist between segments who behave in responsible ways versus those who do not practice responsible behaviors. These segmentation results add to the understanding of Lyons (2004; Journal of Consumer Affairs 38 (1): 56-80) who determined a means of identifying Financially at Risk students (FAR) with payment behavior. Given potentially dangerous effects of targeted credit card marketing to college students, findings about payment behavior of college students will help policymakers, credit card companies and college administrators