N4-aryl substituted thiosemicarbazones derived from 1-indanones as potential anti-tumor agents for breast cancer treatment

SÓLIMO A; SORAIRES SANTACRUZ, MC; LOAIZA PEREZ, AI; BAL DE KIER JOFFÉ, ELISA; FINKIELSZTEIN, L; CALLERO MA

JOURNAL OF CELLULAR PHYSIOLOGY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2017

0021-9541

Breast cancer is globally the most common cancer as well as the leading cause ofcancer deaths in women (Wang et al. 2016). Nowadays, there are severaltreatments for breast cancer. Early stage breast cancers can be completelyresected by surgery. Over time however, the disease may come back evenafter complete resection, which has prompted the development of anadjuvant therapy (post-surgery). Surgery followed by adjuvant treatment hasbeen the gold standard for breast cancer treatment for a long time. Morerecently, neoadjuvant treatment (pre-surgery) has been recognized as animportant strategy in biomarker and target evaluation (Miller et al. 2014).The choice of appropriate therapy depends mainly on the type of tumor.There are currently three prognostic and predictive biomarkers used in routine clinical management of patients with breast cancer. They include estrogen receptor-alpha (ERα), progesterone receptor (PR), and HER2 oncogene/oncoprotein. Unfortunately, a large number of patients are resistant to current treatments, and even those that prove to be sensitive at first may eventually become resistant later. In order to overcome this obstacle, in the last years different molecules have appeared that try to overcome this resistance, optimizing the treatment strategy.Thiosemicarbazones (TSCs) are derivatives of imines which are formed when analdehyde/ketone reacts with a thiosemicarbazide through a condensation reaction.Lately, great emphasis is laid on the synthesis and development of these derivatives because of the wide variety of pharmacological activities they exhibit. TSCs have many biological activities based on their ability to form complexes with metals such as iron, which results in reactive oxygen species (ROS) generation. It has been described that these compounds not only target ribonucleotide reductase (RR) (Finch et al. 1999), but also other intracellular molecules such as N-myc downstream-regulated gene-1 (NDRG1) (Chen et al. 2012) and DNA topoisomerase (top2α) (Yu et al. 2009).Furthermore, since neoplastic cells require a higher amount of essential metals for proliferation than normal cells, metal chelation becomes an interesting strategy when developing anticancer drugs.Finkielsztein et al have developed a series of N4-arylsubstituted TSCs derived from 1-indanones (N4-TSCs) some of which have showed antiviral activity against the bovine viral diarrhea virus (BVDV) (Finkielsztein et al. 2008). In the present study, we investigated the anti-tumor activity of a set of three N4-TSCs: T1 and T2 are new derivatives and T3 was previously described (Soraires Santacruz et al. 2017). The biological activity of these three compounds was assessed in the human breast cancer cell lines MCF-7, MDA-MB 231 and BT 474 which differ in their biomarkers expression pattern. The results showed that only T1 and T2 had cytotoxic effect on all cells lines by apoptosis and necrosis induction mediated by ROS formation and ribonucleotide reductase inhibition. Besides, T1 and T2 inhibited two hallmark traits of cancer cells:their ability to undergo isolated clonal growth and their capacity to migrate. Finally, all N4-TSCs tested decreased the number of cells with mammosphere-forming capacity, suggesting that this kind of compounds could be candidates as potential anti-tumor agents.