Parisi Cristina, Moret Francesca, Fraix Aurore, Menilli Luca, Failla Mariacristina, Sodano Federica, Conte Claudia, Quaglia Fabiana, Reddi Elena, Sortino Salvatore
Department of Drug and Health Sciences, University of Catania, I-95125 Catania, Italy.
Department of Biology, University of Padova, I-35131 Padova, Italy.
ACS Omega. 2022 Feb 24;7(9):7452-7459. doi: 10.1021/acsomega.1c03988. eCollection 2022 Mar 8.
The biological activity of a molecular hybrid () joining doxorubicin (DOX) and an N-nitroso moiety releasing nitric oxide (NO) under irradiation with the biocompatible green light has been investigated against DOX-sensitive (MCF7) and -resistant (MDA-MB-231) breast cancer cells . shows significantly higher cellular internalization than DOX in both cell lines and, in contrast to DOX, does not experience cell efflux in MDR overexpressing MDA-MB-231 cells. The higher cellular internalization of the hybrid seems to be mediated by bovine serum albumin (BSA) as a suitable carrier among serum proteins, according to the high binding constant measured for , which is more than one order of magnitude larger than that reported for DOX. Despite the higher cellular accumulation, is not toxic in the dark but induces remarkable cell death following photoactivation with green light. This lack of dark toxicity is strictly related to the different cellular compartmentalization of the molecular hybrid that, different from DOX, does not localize in the nucleus but is mainly confined in the Golgi apparatus and endoplasmic reticulum and therefore does not act as a DNA intercalator. The photochemical properties of the hybrid are not affected by binding to BSA as demonstrated by the direct detection of NO photorelease, suggesting that the reduction of cell viability observed under light irradiation is a combined effect of DOX phototoxicity and NO release which, ultimately, inhibits MDR1 efflux pump in DOX-resistant cells.
一种分子杂化物（）的生物活性已在生物相容性绿光照射下进行了研究，该杂化物连接了阿霉素（DOX）和一个在照射下释放一氧化氮（NO）的N-亚硝基部分，其针对对DOX敏感的（MCF7）和耐药的（MDA-MB-231）乳腺癌细胞。在两种细胞系中，该杂化物的细胞内化显著高于DOX，并且与DOX不同，在过表达MDR的MDA-MB-231细胞中不会出现细胞外排。根据所测得的该杂化物的高结合常数，其比报道的DOX的结合常数大一个多数量级，杂化物更高的细胞内化似乎是由牛血清白蛋白（BSA）作为血清蛋白中的合适载体介导的。尽管细胞积累更高，但该杂化物在黑暗中无毒，但在绿光光激活后会诱导显著的细胞死亡。这种黑暗毒性的缺乏与分子杂化物不同的细胞区室化密切相关，与DOX不同，它不在细胞核中定位，而是主要局限于高尔基体和内质网，因此不充当DNA嵌入剂。通过直接检测NO光释放证明，杂化物的光化学性质不受与BSA结合的影响，这表明在光照射下观察到的细胞活力降低是DOX光毒性和NO释放的综合作用，最终抑制了耐药细胞中的MDR1外排泵。
