PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation
Abstract Background Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated...
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| creator | Gedaly, Roberto, MD Galuppo, Roberto, MD Musgrave, Yolanda, MD Angulo, Paul, MD Hundley, Jonathan, MD Shah, Malay, MD Daily, Michael F., MD Chen, Changguo, PhD Cohen, Donald A., PhD Spear, Brett T., PhD Evers, B. Mark, MD |
| description | Abstract Background Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells). Materials and methods Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways. Results Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 ( P |
| doi_str_mv | 10.1016/j.jss.2013.05.016 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4390173</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>1_s2_0_S002248041300468X</els_id><sourcerecordid>1443994005</sourcerecordid><originalsourceid>FETCH-LOGICAL-c572t-24179b12241735abd9b4973d03b883dbee871562a297258e2a8f6741fb3ccba03</originalsourceid><addsrcrecordid>eNp9UltrFTEQDqLYY_UH-CL76Muuk8veEApSqhYLCir4NiTZWZt1T3JM9hzovzfbU4v6IASGmXzfN1fGnnOoOPDm1VRNKVUCuKygrnLkAdtw6Ouya1r5kG0AhChVB-qEPUlpguz3rXzMToRsm76RasOGTx8uy7prC-2HIoWoR_LOFHoOnm5jzhc2bI3zenHBF_k5f-2MO3pjMbsDxcJqb7NJC20LS_Nc7GKY3UjxlvWUPRr1nOjZnT1lX99efDl_X159fHd5_uaqtHUrllIo3vaGi9XKWpuhNyrXO4A0XScHQ9S1vG6Ezl2IuiOhu7FpFR-NtNZokKfs7Ki725stDZb8EvWMu-i2Ot5g0A7__vHuGr-HAyrZQ86ZBV7eCcTwc09pwa1Laz_aU9gn5CojewVQZyg_Qm0MKUUa79NwwHU7OGHeDq7bQagxRzLnxZ_13TN-ryMDXh8BlKd0cBQxWUd5tIOLZBccgvuv_Nk_bDs776yef9ANpSnso8_jR45JIODn9TzW6-ASQDXdN_kLqIG1iw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1443994005</pqid></control><display><type>article</type><title>PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Gedaly, Roberto, MD ; Galuppo, Roberto, MD ; Musgrave, Yolanda, MD ; Angulo, Paul, MD ; Hundley, Jonathan, MD ; Shah, Malay, MD ; Daily, Michael F., MD ; Chen, Changguo, PhD ; Cohen, Donald A., PhD ; Spear, Brett T., PhD ; Evers, B. Mark, MD</creator><creatorcontrib>Gedaly, Roberto, MD ; Galuppo, Roberto, MD ; Musgrave, Yolanda, MD ; Angulo, Paul, MD ; Hundley, Jonathan, MD ; Shah, Malay, MD ; Daily, Michael F., MD ; Chen, Changguo, PhD ; Cohen, Donald A., PhD ; Spear, Brett T., PhD ; Evers, B. Mark, MD</creatorcontrib><description>Abstract Background Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells). Materials and methods Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways. Results Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 ( P < 0.001). Interestingly, HuH7 cells were more sensitive to sorafenib than LCSC or PLC cells. Additionally, combination therapy with PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 μM ( P < 0.001; n = 12) and 67% by PKI-587 at 0.1 μM ( P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% ( P = 0.002; n = 12). Conclusions LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro . The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation.</description><identifier>ISSN: 0022-4804</identifier><identifier>EISSN: 1095-8673</identifier><identifier>DOI: 10.1016/j.jss.2013.05.016</identifier><identifier>PMID: 23769634</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antineoplastic Agents - pharmacology ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Drug Therapy, Combination ; Hepatocellular carcinoma ; Humans ; Liver cancer stem cells ; Liver Neoplasms - drug therapy ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; MAP Kinase Signaling System - drug effects ; Morpholines - pharmacology ; Neoplastic Stem Cells - cytology ; Neoplastic Stem Cells - drug effects ; Niacinamide - analogs & derivatives ; Niacinamide - pharmacology ; Phenylurea Compounds - pharmacology ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - metabolism ; PKI-587 ; Proto-Oncogene Proteins c-akt - metabolism ; Proto-Oncogene Proteins p21(ras) - metabolism ; raf Kinases - metabolism ; Signal Transduction - drug effects ; Sorafenib ; Surgery ; TOR Serine-Threonine Kinases - metabolism ; Triazines - pharmacology</subject><ispartof>The Journal of surgical research, 2013-11, Vol.185 (1), p.225-230</ispartof><rights>Elsevier Inc.</rights><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c572t-24179b12241735abd9b4973d03b883dbee871562a297258e2a8f6741fb3ccba03</citedby><cites>FETCH-LOGICAL-c572t-24179b12241735abd9b4973d03b883dbee871562a297258e2a8f6741fb3ccba03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S002248041300468X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23769634$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gedaly, Roberto, MD</creatorcontrib><creatorcontrib>Galuppo, Roberto, MD</creatorcontrib><creatorcontrib>Musgrave, Yolanda, MD</creatorcontrib><creatorcontrib>Angulo, Paul, MD</creatorcontrib><creatorcontrib>Hundley, Jonathan, MD</creatorcontrib><creatorcontrib>Shah, Malay, MD</creatorcontrib><creatorcontrib>Daily, Michael F., MD</creatorcontrib><creatorcontrib>Chen, Changguo, PhD</creatorcontrib><creatorcontrib>Cohen, Donald A., PhD</creatorcontrib><creatorcontrib>Spear, Brett T., PhD</creatorcontrib><creatorcontrib>Evers, B. Mark, MD</creatorcontrib><title>PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation</title><title>The Journal of surgical research</title><addtitle>J Surg Res</addtitle><description>Abstract Background Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells). Materials and methods Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways. Results Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 ( P < 0.001). Interestingly, HuH7 cells were more sensitive to sorafenib than LCSC or PLC cells. Additionally, combination therapy with PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 μM ( P < 0.001; n = 12) and 67% by PKI-587 at 0.1 μM ( P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% ( P = 0.002; n = 12). Conclusions LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro . The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Drug Therapy, Combination</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Liver cancer stem cells</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Morpholines - pharmacology</subject><subject>Neoplastic Stem Cells - cytology</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Niacinamide - pharmacology</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>PKI-587</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>raf Kinases - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Sorafenib</subject><subject>Surgery</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Triazines - pharmacology</subject><issn>0022-4804</issn><issn>1095-8673</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UltrFTEQDqLYY_UH-CL76Muuk8veEApSqhYLCir4NiTZWZt1T3JM9hzovzfbU4v6IASGmXzfN1fGnnOoOPDm1VRNKVUCuKygrnLkAdtw6Ouya1r5kG0AhChVB-qEPUlpguz3rXzMToRsm76RasOGTx8uy7prC-2HIoWoR_LOFHoOnm5jzhc2bI3zenHBF_k5f-2MO3pjMbsDxcJqb7NJC20LS_Nc7GKY3UjxlvWUPRr1nOjZnT1lX99efDl_X159fHd5_uaqtHUrllIo3vaGi9XKWpuhNyrXO4A0XScHQ9S1vG6Ezl2IuiOhu7FpFR-NtNZokKfs7Ki725stDZb8EvWMu-i2Ot5g0A7__vHuGr-HAyrZQ86ZBV7eCcTwc09pwa1Laz_aU9gn5CojewVQZyg_Qm0MKUUa79NwwHU7OGHeDq7bQagxRzLnxZ_13TN-ryMDXh8BlKd0cBQxWUd5tIOLZBccgvuv_Nk_bDs776yef9ANpSnso8_jR45JIODn9TzW6-ASQDXdN_kLqIG1iw</recordid><startdate>20131101</startdate><enddate>20131101</enddate><creator>Gedaly, Roberto, MD</creator><creator>Galuppo, Roberto, MD</creator><creator>Musgrave, Yolanda, MD</creator><creator>Angulo, Paul, MD</creator><creator>Hundley, Jonathan, MD</creator><creator>Shah, Malay, MD</creator><creator>Daily, Michael F., MD</creator><creator>Chen, Changguo, PhD</creator><creator>Cohen, Donald A., PhD</creator><creator>Spear, Brett T., PhD</creator><creator>Evers, B. Mark, MD</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20131101</creationdate><title>PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation</title><author>Gedaly, Roberto, MD ; Galuppo, Roberto, MD ; Musgrave, Yolanda, MD ; Angulo, Paul, MD ; Hundley, Jonathan, MD ; Shah, Malay, MD ; Daily, Michael F., MD ; Chen, Changguo, PhD ; Cohen, Donald A., PhD ; Spear, Brett T., PhD ; Evers, B. Mark, MD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c572t-24179b12241735abd9b4973d03b883dbee871562a297258e2a8f6741fb3ccba03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Drug Therapy, Combination</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Liver cancer stem cells</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Morpholines - pharmacology</topic><topic>Neoplastic Stem Cells - cytology</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Niacinamide - pharmacology</topic><topic>Phenylurea Compounds - pharmacology</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>PKI-587</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Proto-Oncogene Proteins p21(ras) - metabolism</topic><topic>raf Kinases - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Sorafenib</topic><topic>Surgery</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Triazines - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gedaly, Roberto, MD</creatorcontrib><creatorcontrib>Galuppo, Roberto, MD</creatorcontrib><creatorcontrib>Musgrave, Yolanda, MD</creatorcontrib><creatorcontrib>Angulo, Paul, MD</creatorcontrib><creatorcontrib>Hundley, Jonathan, MD</creatorcontrib><creatorcontrib>Shah, Malay, MD</creatorcontrib><creatorcontrib>Daily, Michael F., MD</creatorcontrib><creatorcontrib>Chen, Changguo, PhD</creatorcontrib><creatorcontrib>Cohen, Donald A., PhD</creatorcontrib><creatorcontrib>Spear, Brett T., PhD</creatorcontrib><creatorcontrib>Evers, B. Mark, MD</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of surgical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gedaly, Roberto, MD</au><au>Galuppo, Roberto, MD</au><au>Musgrave, Yolanda, MD</au><au>Angulo, Paul, MD</au><au>Hundley, Jonathan, MD</au><au>Shah, Malay, MD</au><au>Daily, Michael F., MD</au><au>Chen, Changguo, PhD</au><au>Cohen, Donald A., PhD</au><au>Spear, Brett T., PhD</au><au>Evers, B. Mark, MD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation</atitle><jtitle>The Journal of surgical research</jtitle><addtitle>J Surg Res</addtitle><date>2013-11-01</date><risdate>2013</risdate><volume>185</volume><issue>1</issue><spage>225</spage><epage>230</epage><pages>225-230</pages><issn>0022-4804</issn><eissn>1095-8673</eissn><abstract>Abstract Background Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells). Materials and methods Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways. Results Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 ( P < 0.001). Interestingly, HuH7 cells were more sensitive to sorafenib than LCSC or PLC cells. Additionally, combination therapy with PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 μM ( P < 0.001; n = 12) and 67% by PKI-587 at 0.1 μM ( P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% ( P = 0.002; n = 12). Conclusions LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro . The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23769634</pmid><doi>10.1016/j.jss.2013.05.016</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of surgical research, 2013-11, Vol.185 (1), p.225-230 |
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| subjects | Antineoplastic Agents - pharmacology Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Line, Tumor Cell Proliferation - drug effects Drug Therapy, Combination Hepatocellular carcinoma Humans Liver cancer stem cells Liver Neoplasms - drug therapy Liver Neoplasms - metabolism Liver Neoplasms - pathology MAP Kinase Signaling System - drug effects Morpholines - pharmacology Neoplastic Stem Cells - cytology Neoplastic Stem Cells - drug effects Niacinamide - analogs & derivatives Niacinamide - pharmacology Phenylurea Compounds - pharmacology Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism PKI-587 Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins p21(ras) - metabolism raf Kinases - metabolism Signal Transduction - drug effects Sorafenib Surgery TOR Serine-Threonine Kinases - metabolism Triazines - pharmacology |
| title | PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation |
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