Dual targeting of mTORC1 and mTORC2 by INK-128 potently inhibits human prostate cancer cell growth in vitro and in vivo

Jiang, Shangjun; Wang, Shuo

doi:10.1007/s13277-015-3536-6

Cited by 26 publications

(10 citation statements)

References 40 publications

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“… 42 INK-128 has been shown to be potentially efficacious in osteosarcoma, non-small cell lung cancer, B-cell acute lymphoblastic leukemia, colorectal cancer, liver cancer, and pancreatic cancer. 43 – 46 In addition, an additional suppression of AKT may also be observed by INK-128 treatment. 47 Thus, RFA treatment in combination with INK-128 may be a promising strategy for PDAC.…”

Section: Discussionmentioning

confidence: 99%

Radiofrequency ablation in combination with an mTOR inhibitor restrains pancreatic cancer growth induced by intrinsic HSP70

Gao

Yin

et al. 2020

Ther Adv Med Oncol

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Background: Radiofrequency ablation (RFA) is widely used in palliative therapy of malignant cancers. Several studies have shown its applicability and safety for locally advanced pancreatic cancer (LAPC). The objective of this study was to modify the current regimen to improve its therapeutic effect. Methods: Immune cell subtypes and related cytokines were quantified to uncover the immune pattern changes post-RFA treatment. Then, high-throughput proteome analysis was performed to identify differentially expressed proteins associated with RFA, which were further validated in in vitro and in vivo experiments. Finally, a combined therapy was tested in a murine model to observe its therapeutic effect. Results: In preclinical murine models of RFA treatment, no significant therapeutic benefit was observed following RFA treatment. However, the proportion of tumor-infiltrating CD8+ T cells was significantly increased, whereas that of regulatory T cells (Tregs) was decreased post-RFA treatment, which indicated a beneficial anti-tumor environment. To identify the mechanism, high-throughput mass spectrum was obtained that identified heat shock protein 70 (HSP70) as the top differentially expressed protein. HSP70 expression in residual cancer cells was significantly increased post-RFA treatment, which notably promoted pancreatic cancer growth. Elevated HSP70 promoted cell proliferation by activating AKT–mTOR signaling. Finally, RFA treatment combined with an mTOR inhibitor exerted a synergetic repressive effect on tumor growth in the preclinical murine cancer model. Conclusions: RFA treatment in combination with mTOR signaling blockade can not only promote tumor immune response, but also restrain residual cancer cell proliferation. Such a combination may be a promising and effective therapeutic strategy for LAPC patients.

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Section: Discussionmentioning

confidence: 99%

Radiofrequency ablation in combination with an mTOR inhibitor restrains pancreatic cancer growth induced by intrinsic HSP70

Gao

Yin

et al. 2020

Ther Adv Med Oncol

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“…It is clear that in order to defeat CRCP, one compound won't be enough. However, right combination of some promising drugs, like galeterone 26 or INK-128 27 with Mycophenolate Mofetil might represent a viable strategy against CRCP.…”

Section: Discussionmentioning

confidence: 99%

Mycophenolate Mofetil induces c-Jun-N-terminal kinase expression in 22Rv1 cells: an impact on androgen receptor signaling

Ženata¹,

Dvořák²,

Vrzal³

2018

J. Cancer

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Mycophenolate Mofetil (MYC) is a transplant drug used to prevent rejection in heart and kidneys transplant patients. Inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in de novo synthesis of guanosine nucleotides, was considered as a primary target for MYC. Recently, we described that MYC was activates aryl hydrocarbon receptor and it antagonizes glucocorticoid receptor. Here we describe an androgen receptor (AR) as another off-target for MYC.We found that MYC increased basal and dihydrotestosterone (DHT)-inducible AR-dependent luciferase activity in AIZ-AR cells. In the same manner it induced or augmented mRNA level of KLK3 (prostate specific antigen; PSA) in 22Rv1 cells. Herein it displayed a hormetic effect on proliferation activity, since it significantly stimulated proliferation in lower concentrations but inhibited in higher (>1 µg/ml) concentrations in the presence of DHT. In contrast, MYC suppressed DHT-inducible KLK3 mRNA expression and cell proliferation in androgen-dependent LNCaP cells. MYC augmented DHT-inducible nuclear translocation of AR and increased the expression of MAPK8/9 (JNK46/54) resulting in the drop of their phosphorylation status. Moreover, MYC sensitized DHT-treated 22Rv1 cells to JNK-IN-8 mediated growth inhibition with the drop of IC50 from 1425 nM to 84 nM within 24 hrs. In conclusion, we suggest that, castrate-resistant prostate cancers progression might be retarded with the combination of MYC and chemical JNK inhibitors, involving AR-dependent mechanism.

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“…Twenty μg of cytosolic extracts were mixed with the caspase assay buffer [26] and the caspase-3 substrate Ac-DEVD-AFC (15 μg/mL) or the caspase-9 substrate Ac-LEHD-AFC (15 μg/mL) (Calbiochem, Darmstadt, Germany). After incubation, the amount of released AFC was tested by the spectrofluorometer (Thermo-Labsystems, Helsinki, Finland) with excitation of 380 nm and emission wavelength of 460 nm.…”

Section: Caspase-3/-9 Activity Assaymentioning

confidence: 99%

“…The Histone-DNA ELISA assay detects apoptotic cell death by quantifying cytoplasmic histoneassociated DNA fragments [26]. The assay was performed with the instruction from the manufacturer (Roche, Shanghai, China).…”

Section: Histone Dna Apoptosis Elisa Assaymentioning

confidence: 99%

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AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo

Shen¹,

Chen²,

Zhou³

et al. 2018

Cell Physiol Biochem

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Backgrounds/Aims: Bromodomain-containing protein 4 (BRD4) overexpression participates in prostate cancer progression by enhancing the transcriptional activity and expression of several key oncogenes. AZD5153 is a novel BRD4 inhibitor. Methods: Prostate cancer cells were treated with AZD5153. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by [H³] DNA incorporation assay. Cell apoptosis was tested by caspase-3/-9 activity assay, Histone DNA ELISA assay, Annexin V FACS assay and TUNEL staining assay. Cell cycle progression was tested by propidium iodide (PI) FACS assay. Signaling was tested by Western blotting assay. The nude mice PC-3 xenograft model was applied to test AZD5153’s activity in vivo. Results: AZD5153 inhibited proliferation and survival of established and primary prostate cancer cells. AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells. AZD5153 was non-cytotoxic to the prostate epithelial cells. AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, FOSL1 and CDK4) in PC-3 and primary prostate cancer cells. Further studies show that AKT could be the primary resistance factor of AZD5153. Pharmacological inhibition or genetic depletion of AKT induced BRD4 downregulation, sensitizing AZD5153-induced cytotoxicity in PC-3 cells. In vivo, AZD5153 oral administration inhibited PC-3 xenograft tumor growth in nude mice. Its anti-tumor activity was further enhanced with co-treatment of the AKT specific inhibitor MK-2206. Conclusion: Together, our results indicate a promising therapeutic value of the novel BRD4 inhibitor AZD5153 against prostate cancer cells.

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Dual targeting of mTORC1 and mTORC2 by INK-128 potently inhibits human prostate cancer cell growth in vitro and in vivo

Cited by 26 publications

References 40 publications

Radiofrequency ablation in combination with an mTOR inhibitor restrains pancreatic cancer growth induced by intrinsic HSP70

Radiofrequency ablation in combination with an mTOR inhibitor restrains pancreatic cancer growth induced by intrinsic HSP70

Mycophenolate Mofetil induces c-Jun-N-terminal kinase expression in 22Rv1 cells: an impact on androgen receptor signaling

AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo

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