Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/ AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.
Given that 3-phosphoinositide-dependent kinase 1 (PDK1) plays a crucial role in the malignant biological behaviors of a wide range of cancers, we review the influence of PDK1 in breast cancer (BC). First, we describe the power of PDK1 in cellular behaviors and characterize the interaction networks of PDK1. Then, we establish the roles of PDK1 in carcinogenesis, growth and survival, metastasis, and chemoresistance in BC cells. More importantly, we sort the current preclinical or clinical trials of PDK1-targeted therapy in BC and find that, even though no selective PDK1 inhibitor is currently available for BC therapy, the combination trials of PDK1-targeted therapy and other agents have provided some benefit. Thus, there is increasing anticipation that PDK1-targeted therapy will have its space in future therapeutic approaches related to BC, and we hope the novel approaches of targeted therapy will be conducive to ameliorating the dismal prognosis of BC patients.
Chronic myeloid leukemia (CML) is characterized by the presence of chimeric protein BCR-ABL associated with high tyrosine kinase (TK) activity, which leads to cell tumorogenicity, resistance to apoptosis, and differentiation. Gossypol is a natural polyphenolic compound isolated from cottonseed and has antiproliferative activity in a variety of cancer cell lines. (-)Gossypol is proved the potent component. Here we examined the growth inhibitory effect of (-)gossypol and its combination with imatinib in K562 cells. (-)Gossypol inhibited cell growth, promoted apoptosis, induced DeltaPsim loss, and cytochrome C release. Furthermore, (-)gossypol had a synergistic inhibitory effect on growth in K562 cells when combined with imatinib. Enhanced apoptosis, cytochrome C release, and caspase 3 cleavage as well as noticeable decrease of Mcl-1 and Bcl-XL were observed in K562 cells treated with both (-)gossypol and imatinib. These results suggest that (-)gossypol induced apoptosis in K562 cells through a mitochondria pathway and that the combination of imatinib and (-)gossypol might be an effective treatment for CML.
Health-related quality of life (HRQoL) was measured by using SF-12v2. Work productivity impairment was estimated by the Work Productivity and Activity Impairment questionnaire. Information about anticancer drugs was obtained from public data. Results: 1,691 (NHWS-2009/2010) and 1,540 (NHWS-2017) patients with cancer were identified. Changes in baseline characters reflected an aging society in Japan. HRQoL improved significantly from 2009/2010 to 2017 except for vitality although the proportion of insomnia and gastrointestinal problems increased (p,0.05). Presenteeism and total activity impairment worsened (p=0.018). We found annual approval of anticancer drugs as new molecular entity after 2010 was 1.8 times more than before 2010. Moreover, variation of mechanisms of action increased by 1.6 times. Conclusions: No major improvement on overall work productivity impairment of cancer patients has been observed in our latest survey despite the increase in the number of treatment options for cancer. Since cancer mortality rates have been improved, early rehabilitation of cancer patients may result in these differences in trends of HRQoL and work productivity in 2017 compare with 2009/2010. We should continue this type of survey and we will need to measure the social impact of early rehabilitation of cancer patients for multi-evaluation of cancer treatments.
Health-related quality of life (HRQoL) was measured by using SF-12v2. Work productivity impairment was estimated by the Work Productivity and Activity Impairment questionnaire. Information about anticancer drugs was obtained from public data. Results: 1,691 (NHWS-2009/2010) and 1,540 (NHWS-2017) patients with cancer were identified. Changes in baseline characters reflected an aging society in Japan. HRQoL improved significantly from 2009/2010 to 2017 except for vitality although the proportion of insomnia and gastrointestinal problems increased (p,0.05). Presenteeism and total activity impairment worsened (p=0.018). We found annual approval of anticancer drugs as new molecular entity after 2010 was 1.8 times more than before 2010. Moreover, variation of mechanisms of action increased by 1.6 times. Conclusions: No major improvement on overall work productivity impairment of cancer patients has been observed in our latest survey despite the increase in the number of treatment options for cancer. Since cancer mortality rates have been improved, early rehabilitation of cancer patients may result in these differences in trends of HRQoL and work productivity in 2017 compare with 2009/2010. We should continue this type of survey and we will need to measure the social impact of early rehabilitation of cancer patients for multi-evaluation of cancer treatments.
Given that 3-Phosphoinositide-dependent kinase 1 (PDK1) plays a crucial role in malignant biological behaviors of a wide-range of cancers, we further review the influence of PDK1 in breast cancer (BC). First, we describe the power of PDK1 in cellular behaviors and extensively demonstrate the interacting networks of PDK1 via PI3K-dependent/ PI3K-independent pathway. Then we enlighten the roles of PDK1 in carcinogenesis, growth and survival, metastasis, and chemoresistance in BC cells. More important, we sort the current preclinical or clinical trials of PDK1 targeted therapy in BC and find that even though at present no selective PDK1 inhibitor is available for BC therapy, but the combination trials of PDK1 targeted therapy and other agents have demonstrated some benefit. Thus, there is increasing anticipations that PDK1 targeted therapy will have its space in future therapeutic concepts of BC, and we hope to feature PDK1 in BC to the clinic and bring the new promising to patients for targeted therapies.
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