Calcein-acetoxymethy ester enhances the antitumor effects of doxorubicin in nonsmall cell lung cancer by regulating the TopBP1/p53RR pathway

Abstract

Calcein acetoxymethyl ester (calcein-AM) treatment has been reported to exert antitumor effects in certain cancer cells; however, the detailed mechanism of action of calcein-AM in cancers remains unclear, especially in nonsmall cell lung cancer (NSCLC). This study focused on the function and mechanism of action of calcein-AM in NSCLC. We used cell viability assays, western blotting, and EdU proliferation assay combined with calcein-AM treatment or siRNA interference to investigate the role of topoisomerase IIβ binding protein 1 (TopBP1) and p53 in NSCLC chemotherapy. We found that calcein-AM has antitumor effects in lung cancer and enhances the antitumor effects of doxorubicin in NSCLC. Furthermore, we found that TopBP1, which we previously showed was involved in doxorubicin resistance through upregulation of aberrant p53, was involved in calcein-AM-mediated increased doxorubicin sensitivity. Doxorubicin upregulated the expression of aberrant p53. Calcein-AM repressed the expression of TopBP1, which resulted in reduced expression of aberrant p53 and disrupted the antiapoptotic activity mediated by the TopBP1/mutp53 pathway in NSCLC. Together, our findings show that calcein-AM, the cell-permeable derivative of calcein, exerts significant antitumor effects in NSCLC, and can enhance the antitumor effect of doxorubicin by regulating the TopBP1/mutp53 pathway. These findings provide novel insight into lung cancer treatment.

Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy

“…The cell viability dye calcein acetoxymethyl ester (calcein AM) was shown to interfere with TopBP1 oligomerization and p53 binding, resulting in the reactivation of apoptosis and interference with mutant/oncogenic p53 [ 127 ]. Calcein AM showed antitumor activity against breast cancer xenografts [ 127 ] and it increased the antitumor activity of the topoisomerase inhibitor doxorubicin against lung tumor xenografts [ 128 ]. To date no TopBP1 inhibitors have advanced to clinical trials.…”

Identification of Primary and Metastatic Lung Cancer-Related lncRNAs and Potential Targeted Drugs Based on ceRNA Network

“…Likewise, we found 17beta-estradiol (E2), 5-Fluorouracil, Dexamethasone, Vinblastine, 5-aza-2'deoxycytidine (5-Aza-CdR), Tamoxifen, Budesonide, ACTH, Doxorubicin and Paclitaxel could inhibit upregulation of miR-27a-3p and miR-27b-3p. In addition to 17beta-estradiol (E2), all of those drugs were reported the correlation with lung cancer (47)(48)(49)(50)(51)(52)(53)(54)(55), suggesting that 17beta-estradiol (E2) might be used as a potential drug for metastatic LUSC treatment.…”

Oxygen-producing and pH-responsive targeted DNA nanoflowers for enhanced chemo-sonodynamic therapy of lung cancer

“…Chemotherapy is still the primary treatment option for lung cancer therapy nowadays. Among chemotherapeutic drugs, doxorubicin (DOX), an anthracycline antibiotic, has been utilized in numerous studies for the treatment of lung cancer [ [3] , [4] , [5] ]. However, the clinical application of DOX still faces many difficulties that remain to be solved.…”