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The purpose of this study was to preclinically assess the antitumor effects of\n                    <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>\n                    \u20104, a partially purified material of\n                    <jats:italic>Artemisia annua<\/jats:italic>\n                    L., as a monotherapy or in combination with the known mechanistic target of rapamycin complex 1 (\n                    <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>\n                    1) inhibitor, everolimus, against Caki\u20101 (Von Hippel\u2010Lindau (\n                    <jats:styled-content style=\"fixed-case\">VHL<\/jats:styled-content>\n                    )+\/+) and 786\u2010O (\n                    <jats:styled-content style=\"fixed-case\">VHL<\/jats:styled-content>\n                    \u2212\/\u2212) human\n                    <jats:styled-content style=\"fixed-case\">RCC<\/jats:styled-content>\n                    cells.\n                    <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>\n                    \u20104 monotherapy significantly increased tumor growth inhibition and autophagic cell death in\n                    <jats:styled-content style=\"fixed-case\">RCC<\/jats:styled-content>\n                    cells\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Everolimus led to compensatory Akt activation by inhibiting only\n                    <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>\n                    1 signaling pathway. In contrast to everolimus,\n                    <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>\n                    \u20104 enhanced phosphatase and tensin homolog expression and reduced its downstream effector, Akt\/pyruvate kinase muscle isozyme M2 (\n                    <jats:styled-content style=\"fixed-case\">PKM<\/jats:styled-content>\n                    2), leading to decreased expression of glucose transporter 1, which is associated with cancer cell metabolism. The synergistic antitumor and anti\u2010metastatic effects induced by co\u2010administration of\n                    <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>\n                    \u20104 and everolimus involve cell growth inhibition and autophagic cell death via dual targeting of phosphatidylinositol 3\u2010kinase (\n                    <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>\n                    3K)\/Akt\/\n                    <jats:styled-content style=\"fixed-case\">PKM<\/jats:styled-content>\n                    2 and\n                    <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>\n                    1. These findings suggest that\n                    <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>\n                    \u20104 is a novel Akt\/\n                    <jats:styled-content style=\"fixed-case\">PKM<\/jats:styled-content>\n                    2 inhibitor that can overcome the limitation of existing\n                    <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>\n                    inhibitors and can be considered a novel strategy to treat patients with rapidly progressing advanced RCC.\n                  <\/jats:p>","DOI":"10.1002\/cam4.1748","type":"journal-article","created":{"date-parts":[[2018,8,30]],"date-time":"2018-08-30T08:00:24Z","timestamp":1535616024000},"page":"5083-5095","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Novel therapeutic roles of\n                    <scp>MC<\/scp>\n                    \u20104 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt\/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways"],"prefix":"10.1002","volume":"7","author":[{"given":"Ji Yeon","family":"Son","sequence":"first","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University  Suwon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungpil","family":"Yoon","sequence":"additional","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University  Suwon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In Hwan","family":"Tae","sequence":"additional","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University  Suwon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Jin","family":"Park","sequence":"additional","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University  Suwon 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