Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells

Grabinski, Nicole; Ewald, Florian; Hofmann, Bianca T.; Staufer, Katharina; Schumacher, Udo; Nashan, Björn; Jücker, Manfred

doi:10.1186/1476-4598-11-85

Cited by 106 publications

(90 citation statements)

References 49 publications

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“…We aimed in investigating the effect of combined Akt and mTOR inhibition on B-pre ALL cells using the novel allosteric, clinically available pan-Akt inhibitor MK-2206. 29 This combination has been demonstrated to be effective in hepatocellular carcinoma cell lines, 53 cholangiocarcinoma cell lines 38 and in an in vivo model of castration-resistant prostate cancer. 54 Moreover, we used a second combination consisting of CCI-779 and GSK 690693.…”

Section: Dual Mtor/akt Inhibition In B-pre All Lm Neri Et Almentioning

confidence: 99%

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

et al. 2013

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B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/ mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G 0 /G 1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.

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Section: Dual Mtor/akt Inhibition In B-pre All Lm Neri Et Almentioning

confidence: 99%

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

et al. 2013

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“…[10][11][12][13][14] In the clinic, combination chemotherapy for breast cancer is widely used, including drugs such as dasatinib and adriamycin, and has shown excellent results.…”

Section: )mentioning

confidence: 99%

“…9) A growing body of literature has also shown that drug combinations have synergistic anti-cancer effects through the inhibition of these targets. [10][11][12][13][14] In the clinic, combination chemotherapy for breast cancer is widely used, including drugs such as dasatinib and adriamycin, and has shown excellent results. 15) The clinical application of combination chemotherapy covers a wide range of treatments and chemotherapy-related antimetabolite drugs combined with anti-tumor drugs have also had a significant impact, for example, the synergistic anticancer effect of a combination of capecitabine and docetaxel in the treatment of metastatic breast cancer.…”

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confidence: 99%

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

Zhang

Yuan

et al. 2017

Chem. Pharm. Bull.

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Antimetabolite drugs, including the adenosine deaminase inhibitor cladribine, have been shown to induce apoptosis in a variety of cancer cells, and have been widely used in clinical trials of various cancers in conjunction with tyrosine kinase inhibitors (TKIs). Combination treatment with cladribine and gefitinib or dasatinib is expected to have a synergistic inhibitory effect on breast cancer cell growth. Our results demonstrated that the combination treatment had synergistic activity against human breast cancer (MCF-7) cells, enhanced G 2 /M cell arrest and reactive oxygen species (ROS) generation, and increased the loss of mitochondrial membrane potential and cell apoptosis. In addition, the combination treatment decreased Bcl-2 expression. Our results demonstrated that cladribine in combination with gefitinib or dasatinib exerted synergistic anticancer effects on MCF-7 cells by inducing cell cycle arrest, ROS production and apoptosis through the mitochondria-mediated intrinsic pathway.Key words cladribine; gefitinib; dasatinib; breast cancer; combination therapy Breast cancer is the most common malignant tumor and the leading cause of cancer-related deaths in women.1,2) Current treatment for breast cancer includes surgery, radiotherapy and drug therapy, with drug therapy including hormone therapy, chemotherapy and immunotherapy.3,4) The pathogenesis of breast cancer has been studied in-depth, 5) and many drugs have emerged for the treatment of breast cancer, with chemotherapy remaining the mainstay of treatment for breast cancer in addition to surgery. In the clinic, the main chemotherapeutic agents used to treat breast cancer include cisplatin and paclitaxel, docetaxel, curcumin, navelbine, and oxaliplatin. Although these chemotherapy drugs are widely used in the treatment of breast cancer, they often have severe side effects. 6)Recent studies have found that multiple signaling pathways, such as phosphatidylinositol 3-kinase (PI3K) and mitogenactivated protein kinase (MAPK), are involved in breast cancer cell proliferation, and targets of these pathways, such as epidermal growth factor receptor (EGFR), Akt, mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF-1R), human epidermal growth factor receptor-2 (HER2), have become anti-breast cancer drug targets. 7,8) We are known to target anti-breast cancer drugs trastuzumab, lapatinib and so on, but the development of drug resistance in patients has limited their clinical use. With the integration of various disciplines of drug research, the role of multiple targets in biological signaling networks and pathways to achieve appropriate physiological and pathological outcomes has been well studied.9) A growing body of literature has also shown that drug combinations have synergistic anti-cancer effects through the inhibition of these targets. [10][11][12][13][14] In the clinic, combination chemotherapy for breast cancer is widely used, including drugs such as dasatinib and adriamycin, and has shown excellent results. 15)The clinical app...

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“…In addition, PAQR3 negatively regulates the transactivation activity of hypoxia-inducible factor 1α (HIF-1α) by inhibiting formation of the HIF-1α/p300 complex and suppressing VEGF transcription, thereby reducing hypoxia-induced VEGF production (12). Furthermore, recent studies have found that PAQR3 is implicated in a set of human cancers, including clear-cell renal cell carcinoma and colorectal cancer (12,13). However, the significance of altered expression of PAQR3 in HCC has not been fully elucidated due to the lack of studies using fresh human tumor samples.…”

Section: Introductionmentioning

confidence: 99%

Identification of PAQR3 as a new candidate tumor suppressor in hepatocellular carcinoma

Zhang

Ding

et al. 2014

Oncology Reports

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Abstract. Progestin and adipoQ receptor family member III (PAQR3) is a regulator that negatively modulates the Ras/Raf/ MEK/ERK signaling cascade and the GPCR Gβγ subunit signaling pathway. The role of PAQR3 in hepatocellular carcinoma (HCC) has not been elucidated. The present study investigated the expression of PAQR3 and its prognostic value in primary HCC patients. Furthermore, the functional aspects of PAQR3 were also studied using an in vitro cell model. PAQR3 expression was examined in paired HCC and adjacent noncancerous tissues using real-time quantitative RT-PCR (62 pairs) and western blotting (26 pairs). We also analyzed PAQR3 expression in 132 additional HCC samples by immunohistochemistry. The functional impact of PAQR3 on the proliferation and colony formation of an HCC cell line was analyzed by transfecting cells with a full-length PAQR3 expression vector or siRNA targeting PAQR3. The expression of PAQR3 was significantly decreased in the cancer tissues. Clinicopathological analyses showed that the expression of PAQR3 was significantly correlated with expression of serum α-fetoprotein (AFP), mitotic count, tumor size, histological grade and recurrence. Notably, Kaplan-Meier survival curves revealed a correlation between decreased expression of PAQR3 and the poor prognosis of HCC patients. Multivariate analyses showed that PAQR3 expression is an independent prognostic marker for overall and disease-free survival of HCC patients. Furthermore, restoring PAQR3 expression in HCC cells significantly diminished Hep3B cell proliferation and colony formation. Silencing PAQR3 expression in hepatic normal cell line LO2 significantly enhanced cell growth. PAQR3 may play an important role in the progression of HCC and serve as a potential candidate for the targeted therapy of HCC.

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Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells

Cited by 106 publications

References 49 publications

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

Identification of PAQR3 as a new candidate tumor suppressor in hepatocellular carcinoma

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