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

2015 ◽  
Vol 35 (5) ◽  
pp. 1821-1830 ◽  
Author(s):  
Jianzhong Xi ◽  
Miyong Yun ◽  
Duckgue Lee ◽  
Moon-Nyeo Park ◽  
Eun-Ok Kim ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Epigallocatechin Gallate ◽  
Resistant Cell ◽  
Functional Assay ◽  
Drug Resistant ◽  
Transport Activity ◽  
Drug Induced ◽  
P Glycoprotein ◽  
Induced Apoptosis ◽  
Intracellular Region

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.

scholarly journals P-Glycoprotein Mediates Celecoxib-Induced Apoptosis in Multiple Drug-Resistant Cell Lines

2007 ◽  
Vol 67 (10) ◽  
pp. 4915-4923 ◽  
Author(s):  
Ornella Fantappiè ◽  
Michela Solazzo ◽  
Nadia Lasagna ◽  
Francesca Platini ◽  
Luciana Tessitore ◽  
...  
Keyword(s):  
Cell Lines ◽  
Resistant Cell ◽  
Multiple Drug ◽  
Drug Resistant ◽  
P Glycoprotein ◽  
Multiple Drug Resistant ◽  
Induced Apoptosis ◽  
Drug Resistant Cell

IK1 channel activity contributes to cisplatin sensitivity of human epidermoid cancer cells

2008 ◽  
Vol 294 (6) ◽  
pp. C1398-C1406 ◽  
Author(s):  
Elbert L. Lee ◽  
Yuichi Hasegawa ◽  
Takahiro Shimizu ◽  
Yasunobu Okada
Keyword(s):  
Cancer Cells ◽  
Cellular Response ◽  
Physiological Role ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Dominant Negative ◽  
Cation Channels ◽  
Channel Activity ◽  
Kb Cells ◽  
Induced Apoptosis

Cisplatin, a platinum-based drug, is an important weapon against many types of cancer. It induces apoptosis by forming adducts with DNA, although many aspects of its mechanism of action remain to be clarified. Previously, we found a role for the volume-sensitive, outwardly rectifying Cl− channel in cisplatin-induced apoptosis. To investigate the possibility that cation channels also have a role in the cellular response to cisplatin, we examined the activity of cation channels in cisplatin-sensitive KB-3-1 (KB) epidermoid cancer cells by the whole cell patch-clamp method. A cation channel in KB cells, activated by hypotonic stress, was identified as the Ca2+-activated, intermediate-conductance K+ (IK1) channel on the basis of its requirement for intracellular Ca2+, its blockage by the blockers clotrimazole and triarylmethane-34, and its suppression by a dominant-negative construct. Activity of this channel was not observed in KCP-4 cells, a cisplatin-resistant cell line derived from KB cells, and its molecular expression, observed by semiquantitative RT-PCR and immunostaining, appeared much reduced. Cell volume measurements confirmed a physiological role for the IK1 channel as a component of the volume-regulatory machinery in KB cells. A possible role of the IK1 channel in cisplatin-induced apoptosis was investigated. It was found that clotrimazole and triarylmethane-34 inhibited a cisplatin-induced decrease in cell viability and increase in caspase-3/7 activity, whereas 1-ethyl-2-benzimidazolinone, an activator of the channel, had the opposite effect. Thus IK1 channel activity appears to mediate, at least in part, the response of KB cells to cisplatin treatment.

scholarly journals Contribution of Mitochondrial Ion Channels to Chemo-Resistance in Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 761 ◽  
Author(s):  
Roberta Peruzzo ◽  
Ildiko Szabo
Keyword(s):  
Ion Channels ◽  
Cytochrome C ◽  
Cancer Cells ◽  
Cytochrome C Release ◽  
Drug Induced ◽  
Point Of No Return ◽  
Different Types ◽  
Subsequent Activation ◽  
Induced Apoptosis ◽  
Potential Efficiency

Mitochondrial ion channels are emerging oncological targets, as modulation of these ion-transporting proteins may impact on mitochondrial membrane potential, efficiency of oxidative phosphorylation and reactive oxygen production. In turn, these factors affect the release of cytochrome c, which is the point of no return during mitochondrial apoptosis. Many of the currently used chemotherapeutics induce programmed cell death causing damage to DNA and subsequent activation of p53-dependent pathways that finally leads to cytochrome c release from the mitochondrial inter-membrane space. The view is emerging, as summarized in the present review, that ion channels located in this organelle may account in several cases for the resistance that cancer cells can develop against classical chemotherapeutics, by preventing drug-induced apoptosis. Thus, pharmacological modulation of these channel activities might be beneficial to fight chemo-resistance of different types of cancer cells.

scholarly journals Caspase-mediated Cleavage of β-Catenin Precedes Drug-induced Apoptosis in Resistant Cancer Cells

2009 ◽  
Vol 284 (20) ◽  
pp. 13577-13588 ◽  
Author(s):  
Subramanian Senthivinayagam ◽  
Prajna Mishra ◽  
Suresh Kanna Paramasivam ◽  
Srinivas Yallapragada ◽  
Malay Chatterjee ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Drug Induced ◽  
Induced Apoptosis

scholarly journals Cross-Resistance of CD95- and Drug-Induced Apoptosis as a Consequence of Deficient Activation of Caspases (ICE/Ced-3 Proteases)

Blood ◽  
1997 ◽  
Vol 90 (8) ◽  
pp. 3118-3129 ◽  
Author(s):  
Marek Los ◽  
Ingrid Herr ◽  
Claudia Friesen ◽  
Simone Fulda ◽  
Klaus Schulze-Osthoff ◽  
...  
Keyword(s):  
Cell Death ◽  
Drug Treatment ◽  
Tumor Cells ◽  
Anticancer Drugs ◽  
Ex Vivo ◽  
Resistant Cell ◽  
Cross Resistance ◽  
Strong Increase ◽  
Drug Induced ◽  
Induced Apoptosis

Abstract The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. We report here that tumor cells resistant to CD95 (APO-1/Fas) -mediated apoptosis were cross-resistant to apoptosis-induced by anticancer drugs. Apoptosis induced in tumor cells by cytarabine, doxorubicin, and methotrexate required the activation of ICE/Ced-3 proteases (caspases), similarly to the CD95 system. After drug treatment, a strong increase of caspase activity was found that preceded cell death. Drug-induced activation of caspases was also found in ex vivo-derived T-cell leukemia cells. Resistance to cell death was conferred by a peptide caspase inhibitor and CrmA, a poxvirus-derived serpin. The peptide inhibitor was effective even if added several hours after drug treatment, indicating a direct involvement of caspases in the execution and not in the trigger phase of drug action. Drug-induced apoptosis was also strongly inhibited by antisense approaches targeting caspase-1 and -3, indicating that several members of this protease family were involved. CD95-resistant cell lines that failed to activate caspases upon CD95 triggering were cross-resistant to drug-mediated apoptosis. Our data strongly support the concept that sensitivity for drug-induced cell death depends on intact apoptosis pathways leading to activation of caspases. The identification of defects in caspase activation may provide molecular targets to overcome drug resistance in tumor cells.

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