{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T22:46:34Z","timestamp":1785365194038,"version":"3.55.0"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2011,11,7]],"date-time":"2011-11-07T00:00:00Z","timestamp":1320624000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2012,1]]},"abstract":"<jats:p>Alcoholic extract of <jats:italic>Piper<\/jats:italic><jats:italic>betle<\/jats:italic> (<jats:italic>Piper betle<\/jats:italic> L.) leaves was recently found to induce apoptosis of CML cells expressing wild type and mutated Bcr\u2010Abl with imatinib resistance phenotype. Hydroxychavicol (HCH), a constituent of the alcoholic extract of <jats:italic>Piper betle<\/jats:italic> leaves, was evaluated for anti\u2010CML activity. Here, we report that HCH and its analogues induce killing of primary cells in CML patients and leukemic cell lines expressing wild type and mutated Bcr\u2010Abl, including the T315I mutation, with minimal toxicity to normal human peripheral blood mononuclear cells. HCH causes early but transient increase of mitochondria\u2010derived reactive oxygen species. Reactive oxygen species\u2010dependent persistent activation of JNK leads to an increase in endothelial nitric oxide synthase\u2010mediated nitric oxide generation. This causes loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, cleavage of caspase 9, 3 and poly\u2010adenosine diphosphate\u2010ribose polymerase leading to apoptosis. One HCH analogue was also effective <jats:italic>in vivo<\/jats:italic> in SCID mice against grafts expressing the T315I mutation, although to a lesser extent than grafts expressing wild type Bcr\u2010Abl, without showing significant bodyweight loss. Our data describe the role of JNK\u2010dependent endothelial nitric oxide synthase\u2010mediated nitric oxide for anti\u2010CML activity of HCH and this molecule merits further testing in pre\u2010clinical and clinical settings. (<jats:italic>Cancer Sci<\/jats:italic> 2012; 103: 88\u201399)<\/jats:p>","DOI":"10.1111\/j.1349-7006.2011.02107.x","type":"journal-article","created":{"date-parts":[[2011,9,27]],"date-time":"2011-09-27T13:41:30Z","timestamp":1317130890000},"page":"88-99","source":"Crossref","is-referenced-by-count":47,"title":["Expression of Concern: Hydroxychavicol, a <i>Piper betle<\/i> leaf component, induces apoptosis of CML cells through mitochondrial reactive oxygen species\u2010dependent JNK and endothelial nitric oxide synthase activation and overrides imatinib resistance"],"prefix":"10.1111","volume":"103","author":[{"given":"Jayashree B.","family":"Chakraborty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjit 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