Auwal Abdul, Al Banna Md Hasan, Pronoy Tasfik Ul Haque, Hossain M Matakabbir, Rashel K M, Kabir Syed Rashel, Ansary Md Rezaul Haque, Islam Farhadul
Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh.
Department of Chemistry, University of Rajshahi, Rajshahi, 6205, Bangladesh.
Anticancer Agents Med Chem. 2025 Jan 31. doi: 10.2174/0118715206359811241227032311.
Cancer chemotherapy is one of the best ways to treat the patients with cancer as they can remove cancer cells, which can't be remove by radiation or surgery.
Our study is focused on identifying potent chemotherapeutic drugs with minor or no adverse side effects. Therefore, in this study, we aimed to synthesize ethyl 4-[(4-methylbenzyl)oxy] benzoate complex, a macrocyclic aromatic compound followed by testing its antineoplastic activity against Ehrlich ascites carcinoma (EAC) human breast cancer (MCF7) cells.
In vitro and in vivo assays were used for monitoring, cytotoxicity, tumor weight, survival time, tumor cell growth inhibition, and hematological parameters to investigate the anticancer effectiveness of the tested compound. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to examine the expression of growth and apoptotic related genes. Haematological and biochemical parameters were assessed to examine the host toxicity in mice.
The compound exhibited notable anticancer activity against both EAC and MCF7cells. It showed 40.70 and 58.98 % cell growth inhibition at the doses of 0.5 and 1.00 mg/kg, respectively in comparison to that of control EAC-bearing mice (p < 0.0001). The result is comparable with clinically used chemotherapeutic drugs cisplatin (59.2% growth inhibition at the dose of 1.0 mg/kg body weight). A four folds reduction of tumor weight (volume) of treated group at higher dose (1.0 mg/kg/day) was noted in comparison to that of untreated EAC-bearing mice. Also, the mean survival time of treated mice (1.00 mg/kg) increased by more than 83.07% when compared to that of control EAC-bearing mice (p<0.001). In addition, EAC-bearing control mice showed drastic deterioration of RBC, WBC, and % of hemoglobin, however, in the treated mice these parameters were restored towards normal levels. A dose dependent reduction of growth and proliferation of MCF7 cells was noted in compound treated cells. Most importantly, apoptosis of MCF7 was induced followed by activation of pro-apoptotic genes (p53, Bax, Parp, Caspase-3, -8, -9) and inactivation of antiapoptotic, e.g. Bcl2 gene. Toxicological studies reveal that there were changes in hematological (RBC, WBC, % of Hb) and biochemical (serum glucose, cholesterol, creatinine, SGOT, SGPT) parameters during the treatment period, however, the parameters returned towards normal levels after the treatment period, indicating no or minor toxic effect of the compound on the host.
The compound has promising anticancer activity with no or minimum host toxic effects. Thus, it has the potential to be formulated as an effective chemo-agent, however, further preclinical and clinical research is imperative using animal and human models.
癌症化疗是治疗癌症患者的最佳方法之一，因为它可以清除癌细胞，而这些癌细胞无法通过放疗或手术清除。
我们的研究专注于识别具有轻微或无不良副作用的强效化疗药物。因此，在本研究中，我们旨在合成4-[(4-甲基苄基)氧基]苯甲酸乙酯复合物，一种大环芳香化合物，然后测试其对艾氏腹水癌（EAC）和人乳腺癌（MCF7）细胞的抗肿瘤活性。
采用体外和体内试验来监测细胞毒性、肿瘤重量、存活时间、肿瘤细胞生长抑制和血液学参数，以研究受试化合物的抗癌效果。定量逆转录聚合酶链反应（qRT-PCR）用于检测生长和凋亡相关基因的表达。评估血液学和生化参数以检测小鼠的宿主毒性。
该化合物对EAC和MCF7细胞均表现出显著的抗癌活性。与对照EAC荷瘤小鼠相比，在剂量分别为0.5和1.00 mg/kg时，它对细胞生长的抑制率分别为40.70%和58.98%（p < 0.0001）。该结果与临床使用的化疗药物顺铂相当（在剂量为1.0 mg/kg体重时生长抑制率为59.2%）。与未治疗的EAC荷瘤小鼠相比，在较高剂量（1.0 mg/kg/天）下，治疗组的肿瘤重量（体积）减少了四倍。此外，与对照EAC荷瘤小鼠相比，治疗小鼠（1.00 mg/kg）的平均存活时间增加了超过83.07%（p<0.001）。此外，EAC荷瘤对照小鼠的红细胞、白细胞和血红蛋白百分比急剧下降，然而，在治疗小鼠中这些参数恢复到正常水平。在化合物处理的细胞中，观察到MCF7细胞的生长和增殖呈剂量依赖性降低。最重要的是，诱导了MCF7细胞凋亡，随后促凋亡基因（p53、Bax、Parp、Caspase-3、-8、-9）激活，抗凋亡基因如Bcl2失活。毒理学研究表明，治疗期间血液学（红细胞、白细胞、血红蛋白百分比）和生化（血清葡萄糖、胆固醇、肌酐、谷草转氨酶、谷丙转氨酶）参数发生了变化，然而，治疗期后这些参数恢复到正常水平，表明该化合物对宿主无或有轻微毒性作用。
该化合物具有有前景的抗癌活性，对宿主无或有最小毒性作用。因此，它有潜力被配制成一种有效的化疗药物，然而，使用动物和人体模型进行进一步的临床前和临床研究势在必行。
