Elhassanny Ahmed E M, Soliman Eman, Marie Mona, McGuire Paul, Gul Waseem, ElSohly Mahmoud, Van Dross Rukiyah
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Front Oncol. 2020 Jun 17;10:965. doi: 10.3389/fonc.2020.00965. eCollection 2020.
Colorectal cancer (CRC) is a leading cause of cancer death in the United States. Artemisinin derivatives, including the dihydroartemisinin (DHA) monomers, are widely used as clinical agents for the treatment of malaria. Numerous studies demonstrate that these molecules also display antineoplastic activity with minimal toxicity. Of interest, dimeric DHA molecules are more active than their monomeric counterparts. Our previous data showed that the DHA dimer, NSC735847, was a potent inducer of death in different cancer cell types. However, the mechanism of action and activity of NSC735847 in colon cancer cells was not explored. The present study investigated the anticancer activity of NSC735847 and four structurally similar analog in human tumorigenic (HT-29 and HCT-116) and non-tumorigenic (FHC) colon cell lines. NSC735847 was more cytotoxic toward tumorigenic than non-tumorigenic colonocytes. In addition, NSC735847 exhibited greater cytotoxicity and tumor selectivity than the NSC735847 derivatives. To gain insight into mechanisms of NSC735847 activity, the requirement for endoplasmic reticulum (ER) stress and oxidative stress was tested. The data show that ER stress played a key role in the cytotoxicity of NSC735847 while oxidative stress had little impact on cell fate. In addition, it was observed that the cytotoxic activity of NSC735847 required the presence of heme, but not iron. The activity of NSC735847 was then compared to clinically utilized CRC therapeutics. NSC735847 was cytotoxic toward colon tumor cells at lower concentrations than oxaliplatin (OX). In addition, cell death was achieved at lower concentrations in colon cancer cells that were co-treated with folinic acid (Fol), 5-FU (F), and NSC735847 (FolFNSC), than Fol, F, and OX (FolFOX). The selective activity of NSC735847 and its ability to induce cytotoxicity at low concentrations suggest that NSC735847 may be an alternative for oxaliplatin in the FolFOX regimen for patients who are unable to tolerate its adverse effects.
结直肠癌（CRC）是美国癌症死亡的主要原因之一。青蒿素衍生物，包括双氢青蒿素（DHA）单体，被广泛用作治疗疟疾的临床药物。大量研究表明，这些分子还具有抗肿瘤活性且毒性极小。有趣的是，二聚体DHA分子比其单体分子更具活性。我们之前的数据表明，DHA二聚体NSC735847是不同癌细胞类型中强效的死亡诱导剂。然而，尚未探究NSC735847在结肠癌细胞中的作用机制和活性。本研究调查了NSC735847和四种结构相似的类似物在人致瘤性（HT - 29和HCT - 116）和非致瘤性（FHC）结肠细胞系中的抗癌活性。NSC735847对致瘤性结肠细胞的细胞毒性比对非致致瘤性结肠细胞更强。此外，NSC735847比NSC735847衍生物表现出更大的细胞毒性和肿瘤选择性。为深入了解NSC735847的活性机制，测试了内质网（ER）应激和氧化应激的需求。数据表明，ER应激在NSC735847的细胞毒性中起关键作用，而氧化应激对细胞命运影响很小。此外，观察到NSC735847的细胞毒性活性需要血红素的存在，但不需要铁。然后将NSC735847的活性与临床使用的CRC治疗药物进行比较。NSC735847在比奥沙利铂（OX）更低的浓度下对结肠肿瘤细胞具有细胞毒性。此外，与叶酸（Fol）、5 - 氟尿嘧啶（F）和奥沙利铂（OX）联合使用（FolFOX）相比，在与叶酸（Fol）、5 - 氟尿嘧啶（F）和NSC735847联合使用（FolFNSC）的结肠癌细胞中，在更低浓度下即可实现细胞死亡。NSC735847的选择性活性及其在低浓度下诱导细胞毒性的能力表明，对于无法耐受奥沙利铂不良反应的患者，NSC735847可能是FolFOX方案中奥沙利铂的替代药物。
