Quaternary Benzophenanthridine Alkaloids Act as Smac Mimetics and Overcome Resistance to Apoptosis

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Publikace nespadá pod Pedagogickou fakultu, ale pod Lékařskou fakultu. Oficiální stránka publikace je na webu muni.cz.
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KULÍŠKOVÁ Petra VAŠÁTKOVÁ Lucie SLANINOVÁ Iva

Rok publikování 2023
Druh Článek v odborném periodiku
Časopis / Zdroj International Journal of Molecular Sciences
Fakulta / Pracoviště MU

Lékařská fakulta

Citace
www https://www.mdpi.com/1422-0067/24/20/15405
Doi http://dx.doi.org/10.3390/ijms242015405
Klíčová slova apoptosis; benzophenanthridine alkaloids; cancer; cell death; cIAP; Smac mimetic drug resistance; chelerythrine; sanguinarine
Popis Defects in cell death signaling pathways are one of the hallmarks of cancer and can lead to resistance to conventional therapy. Natural products are promising compounds that can overcome this resistance. In the present study we studied the effect of six quaternary benzophenanthridine alkaloids (QBAs), sanguinarine, chelerythrine, sanguirubine, chelirubine, sanguilutine, and chelilutine, on Jurkat leukemia cells, WT, and cell death deficient lines derived from them, CASP3/7/6(-/-) and FADD(-/-), and on solid tumor, human malignant melanoma, A375 cells. We demonstrated the ability of QBAs to overcome the resistance of these deficient cells and identified a novel mechanism for their action. Sanguinarine and sanguirubine completely and chelerythrine, sanguilutine, and chelilutine partially overcame the resistance of CASP3/7/6(-/-) and FADD(-/-) cells. By detection of cPARP, a marker of apoptosis, and pMLKL, a marker of necroptosis, we proved the ability of QBAs to induce both these cell deaths (bimodal cell death) with apoptosis preceding necroptosis. We identified the new mechanism of the cell death induction by QBAs, the downregulation of the apoptosis inhibitors cIAP1 and cIAP2, i.e., an effect similar to that of Smac mimetics.
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