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Int. J. Mol. Sci. 2011, 12(12), 8388-8405; doi:10.3390/ijms12128388

Enhanced Antiproliferative and Apoptotic Response of HT-29 Adenocarcinoma Cells to Combination of Photoactivated Hypericin and Farnesyltransferase Inhibitor Manumycin A

Institute of Biology and Ecology, Faculty of Sciences, P. J. Šafárik University, Moyzesova 11, Košice 041 65, Slovakia
* Author to whom correspondence should be addressed.
Received: 27 October 2011 / Revised: 15 November 2011 / Accepted: 21 November 2011 / Published: 29 November 2011
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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Several photodynamically-active substances and farnesyltransferase inhibitors are currently being investigated as promising anticancer drugs. In this study, the combined effect of hypericin (the photodynamically-active pigment from Hypericum perforatum) and selective farnesyltransferase inhibitor manumycin (manumycin A; the selective farnesyltransferase inhibitor from Streptomyces parvulus) on HT-29 adenocarcinoma cells was examined. We found that the combination treatment of cells with photoactivated hypericin and manumycin resulted in enhanced antiproliferative and apoptotic response compared to the effect of single treatments. This was associated with increased suppression of clonogenic growth, S phase cell cycle arrest, elevated caspase-3/7 activity and time-dependent total cleavage of procaspase-3 and lamin B, cleavage of p21Bax into p18Bax and massive PARP cleavage. Moreover, we found that the apoptosis-inducing factor is implicated in signaling events triggered by photoactivated hypericin. Our results showed the relocalization of apoptosis-inducing factor (AIF) to the nuclei after hypericin treatment. In addition, we discovered that not only manumycin but also photoactivated hypericin induced the reduction of total Ras protein level. Manumycin decreased the amount of farnesylated Ras, and the combination treatment decreased the amount of both farnesylated and non-farnesylated Ras protein more dramatically. The present findings indicate that the inhibition of Ras processing may be the determining factor for enhancing the antiproliferative and apoptotic effects of combination treatment on HT-29 cells.
Keywords: hypericin; manumycin; apoptosis; farnesyltransferase hypericin; manumycin; apoptosis; farnesyltransferase
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Sačková, V.; Kuliková, L.; Kello, M.; Uhrinová, I.; Fedoročko, P. Enhanced Antiproliferative and Apoptotic Response of HT-29 Adenocarcinoma Cells to Combination of Photoactivated Hypericin and Farnesyltransferase Inhibitor Manumycin A. Int. J. Mol. Sci. 2011, 12, 8388-8405.

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