PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-κB

Bark, Hyun; Choi, Cheol-Hee

doi:10.1007/s00280-009-1121-7

Cited by 52 publications

(43 citation statements)

References 27 publications

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“…It is well documented that many transcription factors, such as Ap-1, NF-kB, Akt and STAT3 are involved in activation of MDR1 gene in various cancers [24,25,26,27,28,29]. STAT3 binds to the potential promoter region, +64 and +72 of MDR1 in myeloid leukemia.…”

Section: Discussionmentioning

confidence: 99%

Cinnamaldehyde Derivative (CB-PIC) Sensitizes Chemo-Resistant Cancer Cells to Drug-Induced Apoptosis via Suppression of MDR1 and its Upstream STAT3 and AKT Signalling

Yun¹,

Lee

Park

et al. 2015

Cell Physiol Biochem

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Background/Aims: Our group reported that cinnamaldehyde derivative, (E)-4-((2-(3-oxopop-1-enyl)phenoxy)methyl)pyridinium malonic acid (CB-PIC) induced apoptosis in hypoxic SW620 colorectal cancer cells via activation of AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase (ERK). Herein, sensitizing effect of CB-PIC was investigated in resistant cancer cells such as paclitaxel (PT) resistant lung cancer cells (H460/PT), and Adriamycin (Adr) resistant breast cancer (MCF7/Adr) and colon cancer (HCT15/cos) cells. Methods: Various drug resistant cell lines were treated with CB-PIC, and the signalling pathway and functional assay were explored by Western blot, Rhodamine assay, FACS, RT-PCR and MTT assay. Results: We found that CB-PIC effectively exerted cytotoxicity, increased sub G1 population and the cleaved form of poly (ADP-ribose) polymerase (PARP) and caspase 9 in drug resistant cancer cells. Furthermore, CB-PIC sensitized resistant cancer cells to adriamycin via downregulation of survival proteins such as survivin, Bcl-xL and Bcl-2, along with MDR1 suppression leading to accumulation of drug in the intracellular region. Of note, CB-PIC transcriptionally decreased MDR1 expression via suppression of STAT3 and AKT signalling in three resistant cancer cells with highly expressed P-glycoprotein. Nonetheless, CB-PIC did not affect transport activity of P-glycoprotein in a short time efflux assay, while epigallocatechin gallate (EGCG) accumulated Rhodamine 123 into intracellular region of cell by direct inhibition of MDR1 transport activity. Conclusions: These data demonstrate that CB-PIC suppresses the P-glycoprotein expression through inhibition of STAT3 and AKT signalling to overcome drug resistance in chemo-resistant cancer cells as a potent chemotherapeutic sensitizer.

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Section: Discussionmentioning

confidence: 99%

Cinnamaldehyde Derivative (CB-PIC) Sensitizes Chemo-Resistant Cancer Cells to Drug-Induced Apoptosis via Suppression of MDR1 and its Upstream STAT3 and AKT Signalling

Yun¹,

Lee

Park

et al. 2015

Cell Physiol Biochem

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“…However, there is no effective treatment strategy to override these transporters for clinical therapy. In addition, several receptor-mediated survival signaling pathways, including mitogen-activated protein kinase (MAPK), Akt, mTOR, NF-kB, and Notch pathways, have been linked to the drug resistance of conventional chemotherapy (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling

et al. 2013

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Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133 þ cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133 þ cells has not been investigated methodically. In this study, we revealed that CD133 þ lung cancer cells labeled by a human CD133

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“…The study indicated that GUT-70 may be a useful agent for the treatment of leukemia 107 . Conclusively, it is important to note that, some substituents present on the basic coumarin structure, such as the substituents at position C 4 (28), C 5 (24), C 6 -C 7 (24, 25 and 28), ether at position C 7 (25, 26, 27 and 28) and a [a,b-di(hydroxyisopropyl)dihydrofuran] group at positions C 7 -C 8 (23), exhibit a significant inhibitory effect on P-gp 101 . For example, Jabeen et al 108 reported that heterocyclic substituents at position C 4 or C 3 -C 4 not only enhanced lipophilicity (or log P) but also showed higher inhibitory activity of P-gp.…”

Section: Coumarinsmentioning

confidence: 99%

“…However, inhibition of two or more ABC transporters leads to complicated drug-drug interactions by this class of compounds. These inhibitors include non-immunosuppresive analogs of cyclosporin A, valspodar 23 ; Disomer of verapamil, dexverapamil 24 . Others are MM36 25 , cinchonine 26 and quinine homodimer Q2 27 (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Advances in plant-based inhibitors of P-glycoprotein

Zhou

James

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Multidrug resistance (MDR) has emerged as the main problem in anti-cancer therapy. Although MDR involves complex factors and processes, the main pivot is the expression of multidrug efflux pumps. P-glycoprotein (P-gp) belongs to the family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. It functions in cellular detoxification, pumping a wide range of xenobiotic compounds out of the cell. An attractive therapeutic strategy for overcoming MDR is to inhibit the transport function of P-gp and thus, increase intracellular concentration of drugs. Recently, various types of P-gp inhibitors have been found and used in experiments. However, none of them has passed clinical trials due to their high side-effects. Hence, the search for alternatives, such as plant-based P-gp inhibitors have gained attention recently. Therefore, we give an overview of the source, function, structure and mechanism of plant-based P-gp inhibitors and give more attention to cancer-related studies. These products could be the future potential drug candidates for further research as P-gp inhibitors.

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PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-κB

Abstract: These results indicate that PSC833 not only sensitizes SK-MES-1/DX1000 cells to doxorubicin by enhancing drug accumulation, but also downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB.

Cited by 52 publications

References 27 publications

Cinnamaldehyde Derivative (CB-PIC) Sensitizes Chemo-Resistant Cancer Cells to Drug-Induced Apoptosis via Suppression of MDR1 and its Upstream STAT3 and AKT Signalling

Cinnamaldehyde Derivative (CB-PIC) Sensitizes Chemo-Resistant Cancer Cells to Drug-Induced Apoptosis via Suppression of MDR1 and its Upstream STAT3 and AKT Signalling

Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling

Advances in plant-based inhibitors of P-glycoprotein

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