AMPK is important in cells and the protein has been reported to be primarily found in eukaryotic cells where it exists in the respective heterotrimeric forms [ 1 , 2 ]. Isoforms of the gene have also been reported in humans. In yeast it has been reported that the AMPK, genes have similar function in varied species and are required for the response to glucose starvation [ 3 , 4 ]. Studies have also shown that the gene can be activated over a 100-fold through phosphorylation of threonine 172 within the activation loop of the α subunit [ 5 ]. It is also known that the primary upstream kinase phosphorylation of the activation loop is a complex process and involves the protein kinase LKB1 and its corresponding accessory subunits [ 6 ] where it functions as a tumour suppressor and acts upstream of AMPK [ 7 , 8 ].

Cancer is one of the devastating diseases that affect humans and has been reported to be the main causes of death globally [ 9 ]. Despite the surge in the incidence of the disease, the rate of mortality over the years has decreased due to advances in several therapeutic treatments [ 10 ]. The etiology of cancer has been attributed both to environmental as well as genetic factors [ 11 ]. Many studies in the literature have indicated that diet in relation to certain lifestyles is one of the factors that affect cancer incidence and mortality [ 12 ]. For example, diets based on high intakes of vegetables and fruits have had some strong association with a significant reduction in cancer risk [ 13 , 14 ]. Analyses of these food consumptions have revealed the presence of some bioactive compounds such as the presence of flavonoids, carotenoids, lignans and other phenolic acids that have potential health benefits [ 15 , 16 ]. These compounds act by protecting cells through their antioxidative properties against several environmental conditions, such as exposure to radiation, metals, and other microorganisms that could trigger the oncogenic processes leading to cancer development [ 17 - 19 ]. Furthermore, several studies have been reported elsewhere and have indicated that some of these active compounds have demonstrated their anti-mutagenic and carcinogenic effects against several types of cancers [ 13 , 20 - 22 ].

Studies on AMPK have primarily been involved with metabolism and only limited work unravels its direct role in inflammatory processes and how it relates to the anti-cancer activities with drugs such as metformin, NSAIDs, TCM and other AMPK activators. Additionally, AMPK activation on some oncogenic signaling and biological functions are still unclear and needs further studies. We have synthesized a wide range of phenolic compounds, namely the triphenyl methanol derivatives (TPMs). We have evaluated their respective antioxidative and antiproliferative properties using both lipid and cell models [23-25]. Nevertheless, the use of our synthesized compounds on AMPK activation in humans is limited in literature. Thus, the current studies investigate the potential effect of the TPMs on total- and phospho-AMPKal levels in PC-3 cells. We believe additional studies are necessary to generate more data on the mechanisms and effects of TPMs in modulating the AMPK gene and for any future consideration as effective cancer treatment drug.

TPMs derivatives were evaluated for their antiproliferative activities in PC3 Cells. TRP-TPMs showed comparable antiproliferative activity against PC3, when compared to TRP alone as previously reported [ 22 ]. We then sought in the current studies to determine the efficiencies and optimum dosages of TPMs on total- and phospho-AMPK_a1 in PC3 cells. The cell viability studies indicate that the TPMs at the respective doses did not significantly affect the PC3 cells and beyond the 100 µM following the treatment of cells with the synthesized compounds. TRP-TPMs 2a-e (see Scheme 2 ) showed higher antiproliferative activity compared to the TRP alone. Nevertheless, the results indicate that exposure of PC3 to TPMs at the respective doses had significant effects on total- and phospho-AMPK_a1 in cells. The increases in both total- and phospho-AMPK levels following the exposure were significantly higher for the 24-hr. The findings indicate that TPMs could increase the antioxidative capabilities of the cells to better cope with oxidative stress and/or to prevent and reduce the incidence of prostate cancer. We observed disparities in the controls for total- and phospho-AMPK_a1 ( Figures 1-4 ) proteins for the 12 and 24 studies. This could be due to the differences in incubation times with regards to protein expression [ 32 ]. Secondly, the control values for Figure 3 and Figure 4 reflect the actual quantitative levels of phospho-AMPK_a1 which though were not significantly different from each other but reflect the quantitative gains following the 24 hrs. incubation to the TPMs normalized to the controls. Furthermore, our future studies on the other isoforms of the AMPK gene which are ongoing will help define the ultimate relationship between AMPK and the PI3K/AKT signaling pathway following exposure to the TPMs. We believe such findings lend credence to the mechanisms underlying the effects of TPMs on PC3 cells and may contribute to the scientific knowledge base for any novel treatment strategies targeting AMPK and the PI3K/AKT signaling pathway. We will also seek to use normal cells such as human fibroblasts or HeK293 from kidneys, which may be helpful to elucidate the potential effects and benefits of TRP-TPMs in the said cells in comparison to cancer.

The financial support from Novartis TMCF I HBCU for faculty research is greatly appreciated. The support from the MMC-Vanderbilt-TSU Partners (MVTCP), Grant Number 5U54CA163066-03 and the US Department of Education, Title III Part B, grant number P031B090214 are also acknowledged.