Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites

Alcântara, Laura Maria; Kim, Jun Won; Moraes, Carolina Borsoi; Franco, Caio Haddad; Franzoi, Kathrin D.; Lee, Sukjun; Freitas‐Junior, Lúcio H.; Ayong, Lawrence

doi:10.1016/j.exppara.2013.03.022

Cited by 19 publications

(10 citation statements)

References 55 publications

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“…Thus, CuB may trigger apoptosis by activating the intrinsic apoptosis pathway which results in activation of effector casp-9. Drug resistance is largely mediated through overexpression of MDR, MRP, drug resistance protein, and proteasome subunits, increases in antioxidant defenses, and TOP2 activity; these results have been widely verified (35)(36)(37). The present study identified that the treatment of CuB was able to reverse the MDR of the MCF-7/Adr cells via the downregulation of P-gp and MRP1 (Fig.…”

Section: Discussionsupporting

confidence: 74%

Cucurbitacin B reverses multidrug resistance by targeting CIP2A to reactivate protein phosphatase 2A in MCF-7/Adriamycin cells

et al. 2016

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Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in various tumors. A previous study found that CIP2A expression is associated with doxorubicin (Dox) resistance. In the present study, we investigated whether cucurbitacin B (CuB), a natural anticancer compound found in Cucurbitaceae, reversed multidrug resistance (MDR) and downregulated CIP2A expression in MCF-7/Adriamycin (MCF-7/Adr) cells, a human breast multidrug-resistant cancer cell line. CuB treatment significantly suppressed MCF-7/Adr cell proliferation, and reversed Dox resistance. CuB treatment also induced caspase-dependent apoptosis, decreased phosphorylation of Akt (pAkt). The suppression of pAkt was mediated through CuB-induced activation of protein phosphatase 2A (PP2A). Furthermore, CuB activated PP2A through the suppression of CIP2A. Silencing CIP2A enhanced CuB-induced growth inhibition, apoptosis and MDR inhibition in MCF-7/Adr cells. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A promotes the reversal of MDR induced by CuB.

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Section: Discussionsupporting

confidence: 74%

Cucurbitacin B reverses multidrug resistance by targeting CIP2A to reactivate protein phosphatase 2A in MCF-7/Adriamycin cells

et al. 2016

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“…DDP, as a first-line chemotherapeutic drug for GC patients, especially for advanced stage, activated apoptosis by inducing DNA damage through crosslinking of the DNA (32). However, cancer cells often develop several mechanisms to overcome DDP-induced apoptosis and DNA damage, leading to DDP resistance (33)(34)(35). Therefore, investigation of the molecular mechanism conferring DDP resistance is urgently needed.…”

Section: Discussionmentioning

confidence: 99%

Cucurbitacin B induces autophagy and apoptosis by suppressing CIP2A/PP2A/mTORC1 signaling axis in human cisplatin resistant gastric cancer cells

Duan

et al. 2017

Oncology Reports

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Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple kinds of tumors including gastric cancer (GC). Mammalian target of rapamycin complex 1 (mTORC1) over-activation is detected in GC and many other cancers. Previous study found that CIP2A/mTORC1 controls cell growth and autophagy through direct association. CIP2A plays an 'oncogenic nexus' in several cancer types to participate in the tumorigenic transformation and chemoresistance. In the present study, we investigated whether Cucurbitacin B (CuB), a natural compound found in Cucurbitaceae, can be used in cisplatin (DDP)-resistant human GC cell line SGC7901/DDP. Results demonstrated that CuB treatment significantly suppressed SGC7901/DDP cell proliferation, induced caspase-dependent apoptosis, and autophagy. The activation of autophagy was mediated through CuB-induced inhibition of mTORC1. Furthermore, CuB inhibited mTORC1 via the activation of protein phosphatase 2A (PP2A) which is mediated by CIP2A inhibition. These findings indicated that CuB can inhibit the proliferation, induce caspase-dependent apoptosis, and autophagy of SGC7901/DDP cells by suppressing CIP2A/PP2A/mTORC1 signaling axis. Thus, CuB may be a novel effective candidate to treat DDP-resistant human GC cells.

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“…BODIPY ATP has been used, for example, for imaging exocytosis from ATP-containing vesicles (Akopova et al, 2012) or for determining ATP binding to P-glycoprotein transporters (Alcantara et al, 2013). Most likely BODIPY ATP indiscriminately occupies binding sites of various types of ATP binding proteins present in the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Conformational flexibility of the agonist binding jaw of the human P2X3 receptor is a prerequisite for channel opening

Kowalski

Hausmann

Dopychai

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEIt is assumed that ATP induces closure of the binding jaw of ligand-gated P2X receptors, which eventually results in the opening of the membrane channel and the flux of cations. Immobilization by cysteine mutagenesis of the binding jaw inhibited ATP-induced current responses, but did not allow discrimination between disturbances of binding, gating, subunit assembly or trafficking to the plasma membrane. EXPERIMENTAL APPROACHA molecular model of the pain-relevant human (h)P2X3 receptor was used to identify amino acid pairs, which were located at the lips of the binding jaw and did not participate in agonist binding but strongly approached each other even in the absence of ATP. KEY RESULTSA series of cysteine double mutant hP2X3 receptors, expressed in HEK293 cells or Xenopus laevis oocytes, exhibited depressed current responses to α,β-methylene ATP (α,β-meATP) due to the formation of spontaneous inter-subunit disulfide bonds. Reducing these bonds with dithiothreitol reversed the blockade of the α,β-meATP transmembrane current. Amino-reactive fluorescence labelling of the His-tagged hP2X3 receptor and its mutants expressed in HEK293 or X. laevis oocytes demonstrated the formation of inter-subunit cross links in cysteine double mutants and, in addition, confirmed their correct trimeric assembly and cell surface expression. CONCLUSIONS AND IMPLICATIONSIn conclusion, spontaneous tightening of the binding jaw of the hP2X3 receptor by inter-subunit cross-linking of cysteine residues substituted at positions not directly involved in agonist binding inhibited agonist-evoked currents without interfering with binding, subunit assembly or trafficking.

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Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites

Cited by 19 publications

References 55 publications

Cucurbitacin B reverses multidrug resistance by targeting CIP2A to reactivate protein phosphatase 2A in MCF-7/Adriamycin cells

Cucurbitacin B reverses multidrug resistance by targeting CIP2A to reactivate protein phosphatase 2A in MCF-7/Adriamycin cells

Cucurbitacin B induces autophagy and apoptosis by suppressing CIP2A/PP2A/mTORC1 signaling axis in human cisplatin resistant gastric cancer cells

Conformational flexibility of the agonist binding jaw of the human P2X3 receptor is a prerequisite for channel opening

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