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Cephalostatin 1 Analogues Activate Apoptosis via the Endoplasmic Reticulum Stress Signaling Pathway

Cephalostatin 1 Analogues Activate Apoptosis via the Endoplasmic Reticulum Stress Signaling Pathway

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

Eur J Pharmacol. 2018 Jan 5;818:400-409.

PMID: 29154934

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP402832013	Caspase-4 Inhibitor I - CAS 402832-01-3		402832-01-3	Price

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