Mrusek Marco, Seo Ean-Jeong, Greten Henry Johannes, Simon Michael, Efferth Thomas
Institute of Cultural Anthropology, Johannes Gutenberg University, Mainz, Germany.
Invest New Drugs. 2015 Feb;33(1):32-44. doi: 10.1007/s10637-014-0168-4. Epub 2014 Oct 25.
Ergot alkaloids are psychoactive and vasoconstricting agents of the fungus Claviceps purpurea causing poisoning such as ergotism in medieval times (St. Anthony's Fire). This class of substances also inhibits tumor growth in vitro and in vivo, though the underlying mechanisms are unclear as yet. We investigated six ergot alkaloids (agroclavine, ergosterol, ergocornin E, ergotamine, dihydroergocristine, and 1-propylagroclavine tartrate) for their cytotoxicity towards tumor cell lines of the National Cancer Institute, USA. 1-Propylagroclavine tartrate (1-PAT) revealed the strongest cytotoxicity. Out of 76 clinically established anticancer drugs, cross-resistance was found between the ergot alkaloids and 6/7 anti-hormonal drugs (=85.7 %) and 5/15 DNA-alkylating drugs (=33.3 %). The IC50 values for the six alkaloids were not correlated to well-known determinants of drug resistance, such as proliferative activity (as measured by cell doubling times, PCNA expression, and cell cycle distribution), the multidrug resistance-mediating P-glycoprotein/MDR1 and expression or mutations of oncogenes and tumor suppressor genes (EGFR, RAS, TP53). While resistance of control drugs (daunorubicin, cisplatin, erlotinib) correlated with these classical resistance mechanisms, ergot alkaloids did not. Furthermore, COMPARE and hierarchical cluster analyses were performed of mRNA microarray data to identify genes correlating with sensitivity or resistance to 1-PAT. Twenty-three genes were found with different biological functions (signal transducers, RNA metabolism, ribosome constituents, cell cycle and apoptosis regulators etc.). The expression of only 3/66 neuroreceptor genes correlated with the IC50 values for 1-PAT, suggesting that the psychoactive effects of ergot alkaloids may not play a major role for the cytotoxic activity against cancer cells. In conclusion, the cytotoxicity of ergot alkaloids is not involved in classical mechanisms of drug resistance opening the possibility to bypass resistance and to treat otherwise drug-resistant and refractory tumors. The modes of action are multifactorial, which is a typical feature of many natural compounds.
麦角生物碱是真菌麦角菌产生的具有精神活性和血管收缩作用的物质，在中世纪会导致中毒，如麦角中毒（圣安东尼之火）。这类物质在体外和体内也能抑制肿瘤生长，但其潜在机制尚不清楚。我们研究了六种麦角生物碱（农吉利麦角碱、麦角固醇、麦角角菌素E、麦角胺、二氢麦角隐亭和酒石酸1-丙基农吉利麦角碱）对美国国立癌症研究所肿瘤细胞系的细胞毒性。酒石酸1-丙基农吉利麦角碱（1-PAT）显示出最强的细胞毒性。在76种临床确定的抗癌药物中，发现麦角生物碱与6/7种抗激素药物（=85.7%）和5/15种DNA烷化剂药物（=33.3%）之间存在交叉耐药性。这六种生物碱的IC50值与众所周知的耐药决定因素无关，如增殖活性（通过细胞倍增时间、PCNA表达和细胞周期分布来衡量）、介导多药耐药的P-糖蛋白/MDR1以及癌基因和肿瘤抑制基因（EGFR、RAS、TP53）的表达或突变。虽然对照药物（柔红霉素、顺铂、厄洛替尼）的耐药性与这些经典耐药机制相关，但麦角生物碱却不相关。此外，对mRNA微阵列数据进行了COMPARE和层次聚类分析，以确定与对1-PAT的敏感性或耐药性相关的基因。发现了23个具有不同生物学功能的基因（信号转导器、RNA代谢、核糖体成分、细胞周期和凋亡调节因子等）。只有3/66个神经受体基因的表达与1-PAT的IC50值相关，这表明麦角生物碱的精神活性作用可能对其对癌细胞的细胞毒性活性不起主要作用。总之，麦角生物碱的细胞毒性不涉及经典的耐药机制，这为绕过耐药性以及治疗其他耐药和难治性肿瘤开辟了可能性。其作用方式是多因素的，这是许多天然化合物的典型特征。
