The combined activation of K(Ca)3.1 and inhibition of K(v)11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells.
The combined activation of K(Ca)3.1 and inhibition of K(v)11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells.
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K（CA）3.1的联合激活和K（V）11.1/HERG1电流的抑制作用有助于克服结直肠癌细胞中顺铂的耐药性。
DOI：
10.1038/bjc.2017.392
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发表时间：
2018-01
影响因子：
8.8
通讯作者：
Arcangeli A
中科院分区：
文献类型：
--
作者：
Pillozzi S;D'Amico M;Bartoli G;Gasparoli L;Petroni G;Crociani O;Marzo T;Guerriero A;Messori L;Severi M;Udisti R;Wulff H;Chandy KG;Becchetti A;Arcangeli A
顺铂等铂类药物通常用于癌症治疗。尽管最初有治疗反应，但顺铂治疗通常会导致化疗耐药性的发生。为了确定克服顺铂耐药性的新方法，我们在结直肠癌 (CRC) 细胞上测试了顺铂与 K+ 通道调节剂的组合。通过分子和电生理学技术，在两种 CRC 细胞系（HCT-116 和 HCT-8）中测定了 Ca2+ 激活（KCa3.1，也称为 KCNN4）和电压依赖性（Kv11.1，也称为 KCNH2 或 hERG1）K+ 通道的功能表达。在体外测试了顺铂和几种 K+ 通道调节剂对 K+ 电流、细胞活力、细胞凋亡、细胞周期、增殖、细胞内信号传导和铂摄取的作用。还在模拟顺铂耐药性的小鼠模型中分析了这些效应。与顺铂敏感的 CRC 细胞相比，顺铂耐药的 CRC 细胞表达更高水平的 KCa3.1 和 Kv11.1 通道。在耐药细胞中，KCa3.1激活剂（SKA-31）和Kv11.1抑制剂（E4031）与顺铂具有协同作用，可引发细胞凋亡并抑制增殖。当 KCa3.1 激活和 Kv11.1 抑制相结合时，效果最大。事实上，Riluzole 也产生了类似的结果，它既能激活 KCa3.1，又能抑制 Kv11.1。耐药细胞对顺铂的吸收取决于 KCa3.1 通道活性，因为它被 KCa3.1 激活剂增强。 Kv11.1 阻断导致 KCa3.1 表达增加，从而刺激顺铂的摄取。最后，联合使用 KCa3.1 激活剂和 Kv11.1 抑制剂也克服了体内顺铂耐药性。由于利鲁唑（KCa3.1 激活剂和 Kv11.1 通道抑制剂）已投入临床使用，我们的结果表明该化合物可能在临床上可用于提高顺铂疗效并克服结直肠癌中的顺铂耐药。
Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K+ channel modulators on colorectal cancer (CRC) cells. The functional expression of Ca2+-activated (KCa3.1, also known as KCNN4) and voltage-dependent (Kv11.1, also known as KCNH2 or hERG1) K+ channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K+ channel modulators were tested in vitro for their action on K+ currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance. Cisplatin-resistant CRC cells expressed higher levels of KCa3.1 and Kv11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, KCa3.1 activators (SKA-31) and Kv11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when KCa3.1 activation and Kv11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate KCa3.1 and inhibit Kv11.1. Cisplatin uptake into resistant cells depended on KCa3.1 channel activity, as it was potentiated by KCa3.1 activators. Kv11.1 blockade led to increased KCa3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a KCa3.1 activator and a Kv11.1 inhibitor also overcame Cisplatin resistance in vivo. As Riluzole, an activator of KCa3.1 and inhibitor of Kv11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC.
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影响因子：
8.8
作者：
Lastraioli, E.;Perrone, G.;Sette, A.;Fiore, A.;Crociani, O.;Manoli, S.;D'Amico, M.;Masselli, M.;Iorio, J.;Callea, M.;Borzomati, D.;Nappo, G.;Bartolozzi, F.;Santini, D.;Bencini, L.;Farsi, M.;Boni, L.;Di Costanzo, F.;Schwab, A.;Muda, A. Onetti;Coppola, R.;Arcangeli, A.
通讯作者：
Arcangeli, A.
影响因子：
4
作者：
Muratori L;Petroni G;Antonuzzo L;Boni L;Iorio J;Lastraioli E;Bartoli G;Messerini L;Di Costanzo F;Arcangeli A
通讯作者：
Arcangeli A
DOI：
10.1158/1078-0432.ccr-10-1276
发表时间：
2011-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Khan AJ;Wall B;Ahlawat S;Green C;Schiff D;Mehnert JM;Goydos JS;Chen S;Haffty BG
通讯作者：
Haffty BG
影响因子：
3.6
作者：
Gasparoli, Luca;D'Amico, Massimo;Arcangeli, Annarosa
通讯作者：
Arcangeli, Annarosa
影响因子：
11.2
作者：
Lastraioli, E;Guasti, L;Arcangeli, A
通讯作者：
Arcangeli, A