Suppression of Tumor Growth and Cell Migration by Indole-Based Benzenesulfonamides and Their Synergistic Effects in Combination with Doxorubicin

Abstract

Pharmacological inhibition of the enzyme activity targeting carbonic anhydrases (CAs) demonstrated antiglaucoma and anticancer effects through pH control. Recently, we reported a series of indole-based benzenesulfonamides as potent CA inhibitors. The present study aimed to evaluate the antitumor effects of these compounds against various cancer cell lines, including breast cancer (MDA-MB-231, MCF-7, and SK-BR-3), lung cancer (A549), and pancreatic cancer (Panc1) cells. Overall, more potent cytotoxicity was observed on MCF-7 and SK-BR-3 cells than on lung or pancreatic cancer cells. Among the 15 compounds tested, A6 and A15 exhibited potent cytotoxic and antimigratory activities against MCF-7 and SK-BR-3 cells in the CoCl2-induced hypoxic condition. While A6 and A15 markedly reduced the viability of control siRNA-treated cells, these compounds could not significantly reduce the viability of CA IX-knockdown cells, suggesting the role of CA IX in their anticancer activities. To assess whether these compounds exerted synergism with a conventional anticancer drug doxorubicin (DOX), the cytotoxic effects of A6 or A15 combined with DOX were analyzed using Chou−Talalay and Bliss independence methods. Our data revealed that both A6 and A15 significantly enhanced the anticancer activity of DOX. Among the tested pairs, the combination of DOX with A15 showed the strongest synergism on SK-BR-3 cells. Moreover, this combination further attenuated cell migration compared to the respective drug. Collectively, our results demonstrated that A6 and A15 suppressed tumor growth and cell migration of MCF-7 and SK-BR-3 cells through inhibition of CA IX, and the combination of these compounds with DOX exhibited synergistic cytotoxic effects on these breast cancer cells. Therefore, A6 and A15 may serve as potential anticancer agents alone or in combination with DOX against breast cancer.

The anti‐breast cancer potential of indole/isatin hybrids

“…[ 94 ] Hybrid 55a (IC 50 : 54.1 and 57.9 µM) together with the corresponding regio‐isomer 55b (IC 50 : 56.0 and 49.3 µM) were effective against MCF‐7 and SK‐BR‐3 BC cell lines and blocked CA IX to suppress the growth and migration of the two BC cells. [ 95 ] Notably, combining hybrids 55a,b with doxorubicin showed synergistic effects on BC cells. Accordingly, hybrids 55a,b may be used either alone or in conjunction with doxorubicin to treat BC.…”

Progress of Section “Biochemistry” in 2022

“…A relevant number of papers dealing with this enzyme, its inhibitors, activators and involvement in various diseases have been published in 2022 in this journal [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The first group of contributed materials dealt with the use of this protein for investigations of basic biochemical approaches, such as protein folding [ 7 ], thermodynamic parameters assessment for protein–ligand interactions [ 8 ], bioluminescence resonance energy transfer connected to the binding of the metal ion to apoenzymes [ 9 ], the possibility to evidence chalcogen bonds in the X-ray crystal structures of CA–lig and adduct [ 10 ].…”

“…A large number of CA-related papers dealt with the drug design of CA inhibitors (CAIs) with various applications as anticancer agents (both for treatment and imaging) [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ], antineuropathic pain compounds [ 20 ], mountain sickness leads [ 21 ], antiglaucoma agents [ 22 ] or antibacterials with a novel mechanism of action which, unlike classical antibiotics, target bacterial CAs from various pathogens [ 23 , 24 , 25 ]. Both sulfonamide and non-sulfonamide compounds have been reported in these interesting papers, which highly enrich the number of such pharmacological agents useful for the management of a multitude of pathological conditions [ 2 , 3 ].…”

Hypoxia-Inducible Factor-1: A Novel Therapeutic Target for the Management of Cancer, Drug Resistance, and Cancer-Related Pain

“…The activity of CAIX and CAXII are decreased by VHL [ 41 ] and are significantly induced in hypoxic conditions [ 42 , 43 , 44 ], suggesting that their transcription may be regulated by HIF-1. Numerous CA inhibitors are also emerging as promising agents for the treatment of hypoxic tumors by disrupting HIF-1-regulated pH homeostasis [ 43 , 44 , 45 ]. Thus, regulation of the intracellular pH by HIF-1 also plays an important role in driving tumor proliferation.…”