Publication: Selective inhibition of carbonic anhydrase-IX by sulphonamide derivatives induces pH and reactive oxygen species-mediated apoptosis in cervical cancer HeLa cells
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Date
2018-12-01
Authors
Authors
Koyuncu, Ismail
Gonel, Ataman
KOÇYİĞİT, ABDÜRRAHİM
Temiz, Ebru
Durgun, Mustafa
Supuran, Claudiu T.
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Abstract
Selective inhibition with sulphonamides of carbonic anhydrase (CA) IX reduces cell proliferation and induces apoptosis in human cancer cells. The effect on CA IX expression of seven previously synthesised sulphonamide inhibitors, with high affinity for CA IX, as well as their effect on the proliferation/apoptosis of
cancer/normal cell lines was investigated. Two normal and three human cancer cell lines were used.
Treatment resulted in dose- and time-dependent inhibition of the growth of various cancer cell lines. One
compound showed remarkably high toxicity towards CA IX-positive HeLa cells. The mechanisms of apoptosis induction were determined with Annexin-V and AO/EB staining, cleaved caspases (caspase-3, caspase8, caspase-9) and cleaved PARP activation, reactive oxygen species production (ROS), mitochondrial membrane potential (MMP), intracellular pH (pHi), extracellular pH (pHe), lactate level and cell cycle analysis.
The autophagy induction mechanisms were also investigated. The modulation of apoptotic and autophagic
genes (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin and LC3) was measured using real
time PCR. The positive staining using c-H2AX and AO/EB dye, showed increased cleaved caspase-3, caspase-8, caspase-9, increased ROS production, MMP and enhanced mRNA expression of apoptotic genes,
suggesting that anticancer effects are also exerted through its apoptosis-inducing properties. Our results
show that such sulphonamides might have the potential as new leads for detailed investigations against
CA IX-positive cervical cancers.
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Keywords
Carbonic anhydrase IX, sulphonamide, apoptosis, reactive oxygen species, anticancer agent
Citation
Koyuncu I., Gonel A., KOÇYİĞİT A., Temiz E., Durgun M., Supuran C. T. , -Selective inhibition of carbonic anhydrase-IX by sulphonamide derivatives induces pH and reactive oxygen species-mediated apoptosis in cervical cancer HeLa cells-, Journal of enzyme inhibition and medicinal chemistry, cilt.33, ss.1137-1149, 2018