Synergy between Auraptene, Ionizing Radiation, and Anticancer Drugs in Colon Adenocarcinoma Cells

Abstract

Colorectal cancer is a growing health concern with increasing mortality rates, and resistance to anticancer drugs and radiotherapy is a serious drawback in its treatment. Auraptene is a natural prenyloxycoumarin with valuable anticancer effects. The aim of current study was to determine the synergy between auraptene, ionizing radiation, and chemotherapeutic drugs in colon adenocarcinoma cells for the first time. To do so, HT29 cells were treated with combination of auraptene + cisplatin, + doxorubicin, or + vincristine. Furthermore, cells were pretreated with nontoxic auraptene and then exposed to various doses of X-radiation. Assessment of cell viability not only indicated significant (p < 0.05) synergic effects of auraptene and anticancer agents, also revealed more significant (p < 0.01) increase in the toxicity of applied radiations in auraptene pretreated cells. Interesting synergy between auraptene and radiotherapy was then confirmed by morphological alterations, DAPI staining, and flow cytometric analysis of the cell cycle. Moreover, real-time reverse transcription polymerase chain reaction analysis indicated significant (p < 0.01) overexpression of p21, but not GATA6, in auraptene pretreated cells after radiotherapy, and also significant (p < 0.01) down regulation of CD44 and ALDH1 by auraptene. According to present results, auraptene could be considered as an effective natural coumarin to improve the outcome of current chemoradiotherapy options. Copyright © 2017 John Wiley & Sons, Ltd.

Efficacy of hyperthermia in human colon adenocarcinoma cells is improved by auraptene

“…Assessment of cell viability revealed that non-toxic auraptene significantly increased cytotoxicity of hyperthermia, specifically 24 h after heat shock induction. Although it has been previously indicated that auraptene improved cytotoxicity of anticancer drugs in skin, esophageal and cervical cancers (Kleiner-Hancock et al 2010;Saboor-Maleki et al 2016;Nabekura et al 2008), and also enhanced toxicity of ionizing radiation in colon adenocarcinoma cells (Moussavi et al 2017), this is the first report on improved efficacy of hyperthermia by this coumarin derivative.…”

“…To assess cell viability upon combinatorial treatment, HT29 cells were pretreated with non-toxic auraptene for 3 consecutive days, and then subjected to hyperthermia. Since determined IC 50 of auraptene in HT29 cells was 39 µg/ml after 72 h (Moussavi et al 2017), 10 and 20 µg/ml auraptene, and 0.4% DMSO (relevant control), were administrated in these experiments. As shown in Figure 1, a significant (p<0.01) decrease in cell viability was observed when 20 µg/ml auraptene was used for 72 h, and cells were recovered for 12 h after heat shock induction.…”

“…Moreover, anticancer activities of auraptene have been attributed to its inhibitory effects on breast, prostate, endometrium and liver carcinogenesis (Krishnan et al 2009;Tang et al 2007;Mori et al 2001;Hara et al 2005;Sakata et al 2004), and also apoptogenic activity toward human gastric and leukemia cells (Moon et al 2015;Jun et al 2007). Regarding colon cancer studies, it has been shown that auraptene administration induced chemopreventive effects in animal models (Hayashi et al 2007;Kohno et al 2006, Tanaka et al 2010, presented synergic effects with ionizing radiation (Moussavi et al 2017) and prevented the growth and sphere formation of chemotherapy-resistant colon cancer cells (Epifano et al 2013).…”

“…Currently, one of the main goals of anticancer studies is to deliberate or eradicate cancer cells by innovative combinatorial strategies. Although improved efficacy of anticancer drugs and radiotherapy has been reported in esophageal, cervical and colon carcinoma cells by auraptene (Saboor-Maleki et al 2016;Nabekura et al 2008;Moussavi et al 2017), it is not clear whether this coumarin could induce similar effects on other therapeutic modalities. Accordingly, we aimed to introduce a novel approach against colon adenocarcinoma cells by evaluating cytotoxic effects of hyperthermia alone and in combination with auraptene.…”

<p>pH-Responsive Fluorescence Enhanced Nanogel for Targeted Delivery of AUR and CDDP Against Breast Cancer</p>

“…The synergistic effects of AUR and CDDP can significantly increase the expression of tumor suppressor proteins and enhance the cytotoxicity as reported in previous studies. 2 , 9 , 10 However, the poor water solubility of AUR leads to low bioavailability and little delivery to the target site, while the severe renal toxicity and low selectivity of CDDP make prioritizing chemotherapy for cancers a challenge. 3 , 11 Referring to the advantages of a carrier-free drug delivery system, 12 two biodegradable materials, β-cyclodextrin derivatives (mono-(6-amino-mono-6-deoxy)-β-CD, CD) and hyaluronic acid (HA), were selected as carriers in this experiment to load AUR and CDDP against breast cancer, overcoming the problems of solubility, selectivity, and system toxicity.…”