Anti-Tumorigenic Activity of Chrysin from Oroxylum indicum via Non-Genotoxic p53 Activation through the ATM-Chk2 Pathway

Abstract

The p53 tumor suppressor plays critical roles in cell cycle regulation and apoptotic cell death in response to various cellular stresses, thereby preventing cancer development. Therefore, the activation of p53 through small molecules is an attractive therapeutic strategy for the treatment of cancers retaining wild-type p53. We used a library of 700 Myanmar wild plant extracts to identify small molecules that induce p53 transcriptional activity. A cell-based screening method with a p53-responsive luciferase-reporter assay system revealed that an ethanol extract of Oroxylum indicum bark increased p53 transcriptional activity. Chrysin was isolated and identified as the active ingredient in the O. indicum bark extract. A treatment with chrysin increased p53 protein expression and the p53-mediated expression of downstream target genes, and decreased cell viability in MCF7 cells, but not in p53-knockdown MCF7 cells. We also found that chrysin activated the ATM-Chk2 pathway in the absence of DNA damage. Hence, the inactivation of the ATM-Chk2 pathway suppressed p53 activation induced by chrysin. These results suggest the potential of chrysin as an anti-cancer drug through the activation of p53 without DNA damage.

Ethnopharmacological Inspections of Organic Extract ofOroxylum indicumin Rat Models: A Promising Natural Gift

“…The comparison was done with reference standard drug omeprazole and the ulcer model after treatment with both active fractions and omeprazole showed dramatic gastric mucosal damage conservation. This study also supports previously done experimental studies [46,[84][85][86][87][88][89][90][91][92][93].…”

Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence

“…NOXA promoter-Luc (−198 to +45) was generated by ligating the human NOXA promoter region [26] with pGL4.10. pSUPERretro-p53 was described previously [27]. The TAZ Mission shRNA plasmid (TRCN0000319150) was obtained from Sigma.…”

Oroxylum indicum (L.) Kurz Bignoniaceae

“…Vasanth et al (1991) extracted Ellagic acid, 8, 8 0 Bis-baicalein, Oroxylin A, and Oroxyloside methylester from the root bark. Ali et al (1998) (Nakahara et al 2001(Nakahara et al , 2002Jiwajinda et al 2002;Chen et al 2003Chen et al , 2005Dinda et al 2007;Yuan et al 2008;Hari Babu et al 2010;Liu et al 2010;Majumdar et al 2010;Yan et al 2011Yan et al , 2014Kruger and Ganzera 2012;Cao et al 2013;Li et al 2014a, b;Das et al 2014;Fan et al 2015;Fuentes et al 2015;Rojsanga et al 2017;Sun et al 2017a;Nagasaka et al 2018;Chetry and Bharali 2018;Sithisarn et al 2019;Hemantha et al 2019;Peng et al 2019;Rojsanga et al 2020).…”

“…O. indicum exhibited significant therapeutic activities against various disorders including genotoxic (Tepsuwan et al 1992), anti-inflammatory activity (Ali et al 1998;Tenpe et al 2009;Upaganlawar et al 2009;Siriwatanametanon et al 2010;Doshi et al 2012;Tran et al 2015;Lalrinzuali et al 2016;Begum et al 2019;Dunkhunthod et al 2020), antioxidants (Ng et al 2000;Jiwajinda et al 2002;Palasuwan et al 2005;Zaveri et al 2006;Gupta et al 2008;Kalaivani and Mathew 2009;Mishra et al 2010;Joshi et al 2011;Kumar et al 2011;Singh and Kakkar 2013;Sithisarn et al 2016;Rojsanga et al 2017;Trang et al 2018), anticarcinogenic activity (Nakahara et al 2001(Nakahara et al , 2002Palasuwan et al 2005), antiarthritic activity (Laupattarakasem et al 2003;Karnati et al 2013), anticancer (breast, bladder) (Lambertini et al 2004;Lalou et al 2007;Roy et al 2007;Naveen Kumar et al 2012;He et al 2016;Nagasaka et al 2018;Yang et al 2018;Buranrat et al 2020), antitumor (Costa-Lotufo et al 2005Siriwatanametanon et al 2010), antiprotease activity (Majumdar et al 2010), gastroprotective potential or antiulcer…”