Ibrahim Ahmed S, Sobh Mohamed A M, Eid Hossam Mohammed, Salem Amgad, Elbelasi Hossam Hamza, El-Naggar Mai H, AbdelBar Fatma M, Sheashaa Hussein, Sobh Mohamed A, Badria Farid A
Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt,
Tumour Biol. 2014 Oct;35(10):9941-8. doi: 10.1007/s13277-014-2248-7. Epub 2014 Jul 9.
Cancer chemotherapies have been improved dramatically over the last two decades. In the case of human breast cancer, the combination chemotherapeutic protocol, cyclophosphamide (CPA), doxorubicin (DOX), and 5-fluorouracil (5-FU) (CDF), is often used. Nevertheless, the clinical usefulness of CDF is limited by its remarkably low therapeutic window and frequent eruption of resistance. These limitations prompted our search for a more effective and safe drug candidate that may raise the therapeutic benefits for breast cancer patients. Gingerols' wide therapeutic indices as well as their high efficacy in the suppression of carcinogenesis are well established. However, no thorough study to date has profiled their antibreast cancer activities in depth. Therefore, the aims of the present study are to evaluate the antibreast cancer activities of gingerols in comparison to CDF and to gain insight into the structure activity relationships (SARs) responsible for the observed effect using a breast cancer cell model, MCF-7. Our data revealed that 6-gingerol showed the highest anticancer potency that is superior to that of CDF with IC50 = 30.4 μM. Guided by these results, semisynthetic modifications of 6-gingerol have been carried out to characterize 6-gingerol's SARs. The obtained results showed that the acquisition of free hydroxyl group in the aliphatic side chain of 6-gingerol is essential for the antibreast cancer activity. Likewise, the length of aliphatic side chain in 6-gingerol is optimum for its anticancer activity because any decrease in the side chain length resulted in a dramatic loss of anticancer activity. Additionally, allylation of phenolic group has shown antibreast cancer activity superior to that of 6-gingerol per se. Conversely, methylation or isoprenylation of phenolic group has led to a potential decrease in the anticancer activity, whereas loss of aromaticity resulted in a complete loss of 6-gingerol's cytotoxic activity. Collectively, the present results would simplify drug design to allow safer and more effective antibreast cancer pharmaceuticals to be designed.
在过去二十年中，癌症化疗取得了显著进展。就人类乳腺癌而言，常使用联合化疗方案，即环磷酰胺（CPA）、阿霉素（DOX）和5-氟尿嘧啶（5-FU）（CDF）。然而，CDF的临床效用因其极低的治疗窗口和频繁出现的耐药性而受到限制。这些局限性促使我们寻找一种更有效、更安全的候选药物，以提高乳腺癌患者的治疗效果。姜辣素具有广泛的治疗指数，并且在抑制致癌作用方面具有高效性，这一点已得到充分证实。然而，迄今为止，尚无深入研究全面描述其抗乳腺癌活性。因此，本研究的目的是与CDF相比，评估姜辣素的抗乳腺癌活性，并使用乳腺癌细胞模型MCF-7深入了解产生观察到的效果的构效关系（SARs）。我们的数据显示，6-姜辣素表现出最高的抗癌效力，优于CDF，其IC50 = 30.4 μM。基于这些结果，对6-姜辣素进行了半合成修饰，以表征其SARs。所得结果表明，6-姜辣素脂肪族侧链中游离羟基的获得对于抗乳腺癌活性至关重要。同样，6-姜辣素脂肪族侧链的长度对于其抗癌活性而言是最佳的，因为侧链长度的任何减少都会导致抗癌活性急剧丧失。此外，酚羟基的烯丙基化显示出优于6-姜辣素本身的抗乳腺癌活性。相反，酚羟基的甲基化或异戊二烯基化导致抗癌活性潜在降低，而芳香性的丧失导致6-姜辣素的细胞毒性活性完全丧失。总体而言，目前的结果将简化药物设计，以便设计出更安全、更有效的抗乳腺癌药物。
