DAC models in vitro and in vivo. However, neither AMPK activators

DAC models in vitro and in vivo. However, neither AMPK activators nor mTOR inhibitors were able to mimic these cellular effects in PDAC cells. Clinical trials evaluating PI3K/AKT/mTOR pathway inhibitors in PDAC also failed to demonstrate a survival improvement, suggesting that AMPK-dependent inhibition of mTOR is not the driving mechanism for metformin activity in PDAC. This suggests pathways, such as Sonic Hedgehog, contribute to metformin’s antitumor effect. 16838 Oncotarget Pinocytosis and autophagy inhibitors The finding that survival of RAS-transformed cells depends on autophagy offers a potential approach for inhibition. Hydroxychloroquine is a compound approved for malaria and several rheumatologic diseases that prevents lysosome acidification, thus inhibiting autophagy and macropinocytosis. Several trials testing hydroxychloroquine in patients with PDAC are ongoing. Wolpin et al. reported the results of a phase II study evaluating hydroxychloroquine monotherapy in 20 patients with previously treated metastatic PDAC. Median progressionfree survival and OS were limited. Melatonin, the main pineal hormone that relays light/ dark cycle information to the MedChemExpress 518303-20-3 circadian system, can also be produced in other tissues. Melatonin amphiphilic characteristics allow it to reach any cell, compartment or body fluid. Besides its well-known functions in circadian and seasonal rhythms, melatonin and its metabolites also decrease oxidative stress by acting both as direct free radical scavenger and by stimulating the activity and expression of antioxidant enzymes. Additionally, several other activities have been attributed to melatonin: the regulation of the immune system, the modulation of mitochondrial activity, as well as regulation of cell death and autophagy, and an intrinsic antitumoral activity. Due to the multitude of its actions, a role in maintaining healthy aging has been ascribed to melatonin. Two models have been proposed to explain tumor heterogeneity: the stochastic model that assumes that all cancerous cells have the ability to proliferate and regenerate a tumor and the cancer stem cell model that hypothesizes that similarly to normal tissues, tumors are composed of a mixed population of cells at varying states of differentiation. These differentiated cancer cells are typically unable to initiate a tumor and normally derive PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19858302 from stem-like counterparts with the ability to proliferate indefinitely. Recently, a new cancer stem cell hypothesis www.impactjournals.com/oncotarget 17081 Oncotarget suggests that cancer stem cells could be mostly originated from stochastic effects during DNA replication in normal adult stem cells. Regardless of the true mechanism, cancer stem cells are considered the driving force behind cancer development and progression. It is believed that cancer stem cell differentiation leads to the production of MedChemExpress (-)-Blebbistatin multiple lineages ultimately forming the tumor bulk. In this regard, cancer stem cells have emerged as an important chemotherapeutic target, as their ability to evade treatments provides a likely explanation for tumor re-growth. Although cancer stem cells were only initially described in 1997 for acute myeloid leukemia, they have been further identified and isolated from bone marrow, brain, breast, pancreas, skin, neck, nervous system, colon and prostate cancers. Approaches to eliminate cancer stem cells and avoid tumor re-growth include the depletion of tumor blood supply, differentiation therapies, developmental s.DAC models in vitro and in vivo. However, neither AMPK activators nor mTOR inhibitors were able to mimic these cellular effects in PDAC cells. Clinical trials evaluating PI3K/AKT/mTOR pathway inhibitors in PDAC also failed to demonstrate a survival improvement, suggesting that AMPK-dependent inhibition of mTOR is not the driving mechanism for metformin activity in PDAC. This suggests pathways, such as Sonic Hedgehog, contribute to metformin’s antitumor effect. 16838 Oncotarget Pinocytosis and autophagy inhibitors The finding that survival of RAS-transformed cells depends on autophagy offers a potential approach for inhibition. Hydroxychloroquine is a compound approved for malaria and several rheumatologic diseases that prevents lysosome acidification, thus inhibiting autophagy and macropinocytosis. Several trials testing hydroxychloroquine in patients with PDAC are ongoing. Wolpin et al. reported the results of a phase II study evaluating hydroxychloroquine monotherapy in 20 patients with previously treated metastatic PDAC. Median progressionfree survival and OS were limited. Melatonin, the main pineal hormone that relays light/ dark cycle information to the circadian system, can also be produced in other tissues. Melatonin amphiphilic characteristics allow it to reach any cell, compartment or body fluid. Besides its well-known functions in circadian and seasonal rhythms, melatonin and its metabolites also decrease oxidative stress by acting both as direct free radical scavenger and by stimulating the activity and expression of antioxidant enzymes. Additionally, several other activities have been attributed to melatonin: the regulation of the immune system, the modulation of mitochondrial activity, as well as regulation of cell death and autophagy, and an intrinsic antitumoral activity. Due to the multitude of its actions, a role in maintaining healthy aging has been ascribed to melatonin. Two models have been proposed to explain tumor heterogeneity: the stochastic model that assumes that all cancerous cells have the ability to proliferate and regenerate a tumor and the cancer stem cell model that hypothesizes that similarly to normal tissues, tumors are composed of a mixed population of cells at varying states of differentiation. These differentiated cancer cells are typically unable to initiate a tumor and normally derive PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19858302 from stem-like counterparts with the ability to proliferate indefinitely. Recently, a new cancer stem cell hypothesis www.impactjournals.com/oncotarget 17081 Oncotarget suggests that cancer stem cells could be mostly originated from stochastic effects during DNA replication in normal adult stem cells. Regardless of the true mechanism, cancer stem cells are considered the driving force behind cancer development and progression. It is believed that cancer stem cell differentiation leads to the production of multiple lineages ultimately forming the tumor bulk. In this regard, cancer stem cells have emerged as an important chemotherapeutic target, as their ability to evade treatments provides a likely explanation for tumor re-growth. Although cancer stem cells were only initially described in 1997 for acute myeloid leukemia, they have been further identified and isolated from bone marrow, brain, breast, pancreas, skin, neck, nervous system, colon and prostate cancers. Approaches to eliminate cancer stem cells and avoid tumor re-growth include the depletion of tumor blood supply, differentiation therapies, developmental s.