Abstract
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.
Highlights
Hypericin is a photodynamic pigment first isolated from the plant Hypericum perforatum L., commonly known as St
Besides an enhanced antiproliferative and apoptotic response of HT-29 cells to combination treatment with photoactivated hypericin and manumycin, we discovered new players in the signaling machinery triggered by photoactivated hypericin, namely an apoptosis-inducing factor (AIF) and Ras
Colon adenocarcinoma cells HT-29 were exposed to combination treatment with photoactivated hypericin and Ras farnesyltransferase inhibitor manumycin
Summary
Hypericin is a photodynamic pigment first isolated from the plant Hypericum perforatum L., commonly known as St. The effectiveness of hypericin-mediated photodynamic therapy was improved by the use of PD169316, a p38α MAPK inhibitor in human cervix carcinoma cells and human bladder cancer cells [8] and by diazepam in glioma cells [9]. Several studies have demonstrated the enhanced cytotoxic or apoptotic effects on various cancer cell lines as a consequence of the combination of manumycin and paclitaxel [18], methoxyamine [27]. The effective combination of photodynamically-active drug and selective farnesyltransferase inhibitor was investigated for the first time. Manumycin, we discovered new players in the signaling machinery triggered by photoactivated hypericin, namely an apoptosis-inducing factor (AIF) and Ras. Our results indicate the possibility of new effective combination of two natural products, the photodynamically-active drug and farnesyltransferase inhibitor, as a new modality approach for anticancer therapies in the future
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