{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:53:19Z","timestamp":1792806799805,"version":"4.5.0"},"reference-count":48,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2012,7,9]],"date-time":"2012-07-09T00:00:00Z","timestamp":1341792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2013,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pancreatic cancer is almost always fatal, in part because of its delayed diagnosis, poor prognosis, rapid progression and chemoresistance. Oncogenic proteins are stabilized by the Hsp90, making it a potential therapeutic target. We investigated the oxidative stress\u2010mediated dysfunction of Hsp90 and the hindrance of its chaperonic activity by a carbazole alkaloid, mahanine, as a strategic therapeutic in pancreatic cancer. Mahanine exhibited antiproliferative activity against several pancreatic cancer cell lines through apoptosis. It induced early accumulation of reactive oxygen species (ROS) leading to thiol oxidation, aggregation and dysfunction of Hsp90 in MIAPaCa\u20102. <jats:italic>N<\/jats:italic>\u2010acetyl\u2010<jats:sc>L<\/jats:sc>\u2010cysteine prevented mahanine\u2010induced ROS accumulation, aggregation of Hsp90, degradation of client proteins and cell death. Mahanine disrupted Hsp90\u2010Cdc37 complex in MIAPaCa\u20102 as a consequence of ROS generation. Client proteins were restored by MG132, suggesting a possible role of ubiquitinylated protein degradation pathway. Surface plasmon resonance study demonstrated that the rate of interaction of mahanine with recombinant Hsp90 is in the range of seconds. Molecular dynamics simulation showed its weak interactions with Hsp90. However, no disruption of the Hsp90\u2010Cdc37 complex was observed at an early time point, thus ruling out that mahanine directly disrupts the complex. It did not impede the ATP binding pocket of Hsp90. Mahanine also reduced <jats:italic>in vitro<\/jats:italic> migration and tube formation in cancer cells. Further, it inhibited orthotopic pancreatic tumor growth in nude mice. Taken together, these results provide evidence for mahanine\u2010induced ROS\u2010mediated destabilization of Hsp90 chaperone activity resulting in Hsp90\u2010Cdc37 disruption leading to apoptosis, suggesting its potential as a specific target in pancreatic cancer.<\/jats:p>","DOI":"10.1002\/ijc.27687","type":"journal-article","created":{"date-parts":[[2012,6,22]],"date-time":"2012-06-22T19:59:54Z","timestamp":1340395194000},"page":"695-706","source":"Crossref","is-referenced-by-count":64,"title":["Oxidative inhibition of Hsp90 disrupts the super\u2010chaperone complex and attenuates pancreatic adenocarcinoma <i>in vitro<\/i> and <i>in vivo<\/i>"],"prefix":"10.1002","volume":"132","author":[{"given":"Sayantani","family":"Sarkar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devawati","family":"Dutta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suman 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