Details

Autor(en) / Beteiligte

• Tahtamouni, Lubna H.
• Nawasreh, Mansour M.
• Al-Mazaydeh, Zainab A.
• Al-Khateeb, Rema A.
• Abdellatif, Reem N.
• Bawadi, Randa M.
• Bamburg, James R.
• Yasin, Salem R.

Titel

Cephalostatin 1 analogues activate apoptosis via the endoplasmic reticulum stress signaling pathway

Ist Teil von

• European journal of pharmacology, 2018-01, Vol.818, p.400-409

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• The current study was conducted to compare the cytotoxicity of two stereospecific cephalostatin 1 analogues (CAs) against several human normal cell types and cancer cell lines and to determine their cytotoxic mechanism. Both CA analogues induced apoptosis and were cytotoxic with 50% growth inhibition (GI50) at ~1µM or less in six human cancer cell lines but neither analogue at 10µM killed more than 14% of any of three types of normal human cells suggesting their cytotoxicity is cancer-specific. CA treatment inhibited clonogenic tumor growth and activated caspase 3 and 9 but not caspase 8. CA-induced apoptosis was inhibited by the pan caspase inhibitor indicating the importance of caspase activation. CA treatment released smac/DIABLO but not cytochrome c from mitochondria and induced phosphorylation of eIF-2 and the activation of procaspase 4 in cancer cells, similar to cell treatment with thapsigargin, a known endoplasmic reticulum (ER) stress inducer. Finally, cells pretreated with a caspase 4 inhibitor were resistant to CA-induced apoptosis. In conclusion, both CAs induced apoptosis by triggering ER stress. Because of their ease of synthesis and low GI50, these cephalostatin analogues represent promising anticancer drugs. [Display omitted]