Sulfocoumarins, specific carbonic anhydrase IX and XII inhibitors, interact with cancer multidrug resistant phenotype through pH regulation and reverse P-glycoprotein mediated resistance.
2019
Аутори:
Podolski-Renić, AnaDinić, Jelena
Stanković, Tijana
Jovanović, Mirna
Ramović, Amra
Pustenko, Aleksandrs
Žalubovskis, Raivis
Pešić, Milica
Тип документа:
Чланак у часопису (Објављена верзија)
,
© 2019 Elsevier B.V.
Метаподаци
Приказ свих података о документуАпстракт:
New 6-triazolyl-substituted sulfocoumarins were described as potent inhibitors of the transmembrane human carbonic anhydrase isoforms, CAIX and CAXII. These membrane associated enzymes that maintain pH and CO2 homeostasis are involved in cancer progression, invasion, and resistance to therapy. Recently, it was shown that CAXII expression associates with the expression of P-glycoprotein in multidrug resistant cancer cells. CAXII regulates P-glycoprotein activity by maintaining high intracellular pHi. In this study, the activity of three new sulfocoumarins was evaluated in three sensitive and corresponding multidrug resistant cancer cell lines with increased P-glycoprotein expression (non-small cell lung carcinoma, colorectal carcinoma and glioblastoma). Compound 3 showed the highest potential for cancer cell growth inhibition in all tested cell lines. Flow cytometric analyses showed that compound 3 induced intracellular acidification, cell cycle arrest in G2/M phase and necrosis in non-small cell lung carcinoma cells. Compound 3 demonstrated irreversible, concentration- and time-dependent inhibition of P-glycoprotein activity in multidrug resistant non-small cell lung carcinoma cells. The suppression of P-glycoprotein activity was accompanied with increased P-glycoprotein expression suggesting a compensatory mechanism of multidrug resistant cancer cells. In addition, compound 3 was able to sensitize multidrug resistant non-small cell lung carcinoma cells to doxorubicin. Overall, results imply that compound 3 has multidrug resistance modulating effect through intracellular acidification and subsequent inhibition of P-glycoprotein activity.
Кључне речи:
Carbonic anhydrase; Intracellular pH; Multidrug resistance; P-glycoprotein; SulfocoumarinsИзвор:
European Journal of Pharmaceutical Sciences, 2019, 138, 105012-Финансирање / пројекти:
- Идентификација молекуларних маркера за предикцију прогресије тумора, одговора на терапију и исхода болести (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- COST Action CM1407 “Challenging organic syntheses inspired by nature — from natural products chemistry to drug discovery”
- COST Action CA17104 “New diagnostic and therapeutic tools against multidrug resistant tumors”
DOI: 10.1016/j.ejps.2019.105012
PubMed: 31330259
WoS: 000485819800006
Scopus: 2-s2.0-85069886794
URI
https://www.sciencedirect.com/science/article/pii/S0928098719302751?dgcid=coauthorhttps://radar.ibiss.bg.ac.rs/handle/123456789/3441