Wen Jie, Zhao Lingmao, Li Zhuohan, Pi Chao, Feng Xianhu, Shi Peng, Yang Hongru, Chen Ligang, Wang Xiaodong, Liu Furong, Wei Yumeng, Zhao Ling
Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, China.
Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China.
Front Pharmacol. 2024 Nov 12;15:1464626. doi: 10.3389/fphar.2024.1464626. eCollection 2024.
Chemotherapy remains the first choice of treatment for colon cancer despite the inevitable adverse effects. Curcumin (CU) possesses antitumor activity but has poor aqueous solubility, low bioavailability, and weak activity. To address this, nine novel monocarbonyl CU analogues were designed, synthesized, and evaluated in the present study. Among them, CA8 exhibited the highest water solubility, which was approximately 2.37 × 10 times that of CU. In addition, compared with CU, its cytotoxicity on Caco-2 cells (19.2 times/48 h) was stronger. Of note, CA8 arrestedthe cell cycle of Caco-2 cells at the G2/M phase and induced apoptosis. Meanwhile, acute toxicity experiments indicated that KM mice tolerated CA8 for up to 300 mg/kg CA8 (oral administration) and 50 mg/kg CA8 (intraperitoneal injection). The oral administration of CA8 to Sprague Dawley rats exhibited higher AUC (0-t) (6.23-fold) and longer MRT (0-t) (3.35-fold) than that of CU. CA8 also inhibited the proliferation and angiogenesis of tumor cells more than CU and tegafur. Finally, CA8 may exert anti-tumor effects through the activation of JNK pathway and inhibition of AKT pathway. These results suggest that CA8 is a safe and highly effective new drug for colon cancer treatment.
尽管化疗不可避免地会产生副作用，但它仍然是结肠癌治疗的首选方法。姜黄素（CU）具有抗肿瘤活性，但水溶性差、生物利用度低且活性弱。为了解决这个问题，本研究设计、合成并评估了九种新型单羰基CU类似物。其中，CA8表现出最高的水溶性，约为CU的2.37×10倍。此外，与CU相比，其对Caco-2细胞的细胞毒性更强（48小时内为19.2倍）。值得注意的是，CA8使Caco-2细胞的细胞周期停滞在G2/M期并诱导细胞凋亡。同时，急性毒性实验表明，昆明小鼠对高达300mg/kg CA8（口服给药）和50mg/kg CA8（腹腔注射）具有耐受性。对Sprague Dawley大鼠口服CA8的AUC（0-t）（6.23倍）和MRT（0-t）（3.35倍）均高于CU。CA8对肿瘤细胞增殖和血管生成的抑制作用也比CU和替加氟更强。最后，CA8可能通过激活JNK通路和抑制AKT通路发挥抗肿瘤作用。这些结果表明，CA8是一种安全有效的结肠癌治疗新药。
