Activity of the <scp>mTOR</scp> inhibitor RAD001, the dual <scp>mTOR</scp> and PI3‐kinase inhibitor BEZ235 and the PI3‐kinase inhibitor BKM120 in hepatocellular carcinoma

Kirstein, Martha M.; Boukouris, Aristeidis E.; Pothiraju, D.; Buitrago‐Molina, Laura Elisa; Marhenke, Silke; Schütt, J.; Orlik, Johanna; Kühnel, Florian; Hegermann, Jan; Manns, Michael P.; Vogel, Arndt

doi:10.1111/liv.12126

Cited by 39 publications

(48 citation statements)

References 38 publications

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“…These results are in accordance with the results of Shoji et al and Oishi et al, who used commercial EC cell lines and ovarian clear cell carcinoma cell lines, respectively [17,30]. In hepatocellular carcinoma, however, Kirstein et al indicated that NVP-BKM120 has a higher antitumor activity compared to RAD001 (mTORC1 inhibitor) and NVP-BEZ235 [31].…”

Section: Discussionsupporting

confidence: 92%

Dual blockade of PI3K/AKT/mTOR (NVP-BEZ235) and Ras/Raf/MEK (AZD6244) pathways synergistically inhibit growth of primary endometrioid endometrial carcinoma cultures, whereas NVP-BEZ235 reduces tumor growth in the corresponding xenograft models

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Coenegrachts

et al. 2015

Gynecologic Oncology

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Section: Discussionsupporting

confidence: 92%

Dual blockade of PI3K/AKT/mTOR (NVP-BEZ235) and Ras/Raf/MEK (AZD6244) pathways synergistically inhibit growth of primary endometrioid endometrial carcinoma cultures, whereas NVP-BEZ235 reduces tumor growth in the corresponding xenograft models

Schrauwen

Depreeuw

Coenegrachts

et al. 2015

Gynecologic Oncology

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“…For everolimus it was expected that reduced mTOR activation would lead to reduced transcription of glycolytic enzymes and therefore a shift to mitochondrial respiration [23]. In contrast, we observed that everolimus inhibits mitochondrial respiration, which was not compensated by an enhanced glycolysis rate, as previously reported for hepatocellular carcinoma cells as well [24]. In human pancreatic cancer cell lines, however, everolimus treatment reduced the rate of glycolysis.…”

Section: Discussionsupporting

confidence: 75%

Anti-tumor effects of everolimus and metformin are complementary and glucose-dependent in breast cancer cells

et al. 2017

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BackgroundClinical efficacy of the mTOR inhibitor everolimus is limited in breast cancer and regularly leads to side-effects including hyperglycemia. The AMPK inhibitor and anti-diabetic drug metformin may counteract everolimus-induced hyperglycemia, as well as enhancing anti-cancer efficacy. We investigated the glucose-dependent growth-inhibitory properties of everolimus, metformin and the combination in breast cancer cell lines.MethodsThe breast cancer cell lines MCF-7, MDA-MB-231 and T47D were cultured in media containing 11 mM or 2.75 mM glucose with 21% or 1% oxygen. Everolimus and metformin treated cells were subjected to cytotoxicity and clonogenic assays, western blotting, FACS and metabolic measurements.ResultsEverolimus was less effective in MCF7 cells under low glucose conditions compared to high glucose conditions (IC50 of >50 nM vs 29.1 ± 1.4 nM) in a short-term survival assay, while sensitivity of MDA-MB-231 and T47D cells to everolimus was lost under low glucose conditions. In contrast, metformin was more effective in low than in high glucose conditions in MCF7 (IC50 of 1.8 ± 1.2 mM vs >5 mM) and MDA-MB231 cells (1.5 ± 1.3 mM vs 2.6 ± 1.2 mM). Metformin sensitivity of T47D cells was independent of glucose concentrations. Everolimus combined with metformin additively inhibited cell survival, clonogenicity, mTOR signaling activity and mitochondrial respiration. These effects were not the result of enhanced autophagy or apoptosis induction. Similar results were observed under hypoxic conditions.ConclusionMetformin-induced effects are additive to the anti-proliferative and colony inhibitory properties of everolimus through inhibition of mitochondrial respiration and mTOR signaling. These results warrant further in vivo investigation of everolimus combined with metformin as a putative anti-cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3230-8) contains supplementary material, which is available to authorized users.

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“…$ indicates bins containing values that were reported in literature as IC 50 > x μM ( x =position of indicated bin). Values were extracted from refs 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47.…”

Section: Figurementioning

confidence: 99%

Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

et al. 2017

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BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K. Crystal structures of BKM120 and derivatives in complex with tubulin and PI3K provide insights into the selective mode of action of this class of drugs. Our results raise concerns over BKM120's generally accepted mode of action, and provide a unique mechanistic basis for next-generation PI3K inhibitors with improved safety profiles and flexibility for use in combination therapies.

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Activity of the mTOR inhibitor RAD001, the dual mTOR and PI3‐kinase inhibitor BEZ235 and the PI3‐kinase inhibitor BKM120 in hepatocellular carcinoma

Abstract: In this study, BKM120 showed the strongest antitumour activity. Our findings suggest impairment of mitochondrial function as a relevant mechanism of BKM120. Moreover, combination of PI3K and mTOR inhibitors with cytotoxic agents could be promising option for non-cirrhotic HCC patients.

Cited by 39 publications

References 38 publications

Dual blockade of PI3K/AKT/mTOR (NVP-BEZ235) and Ras/Raf/MEK (AZD6244) pathways synergistically inhibit growth of primary endometrioid endometrial carcinoma cultures, whereas NVP-BEZ235 reduces tumor growth in the corresponding xenograft models

Dual blockade of PI3K/AKT/mTOR (NVP-BEZ235) and Ras/Raf/MEK (AZD6244) pathways synergistically inhibit growth of primary endometrioid endometrial carcinoma cultures, whereas NVP-BEZ235 reduces tumor growth in the corresponding xenograft models

Anti-tumor effects of everolimus and metformin are complementary and glucose-dependent in breast cancer cells

Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

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