Piperlongumine

Piperlongumine is a natural alkaloid compound extracted from Piper longum L., which has multiple pharmacological activities, including anti-tumor, lipid metabolism regulation, anti-platelet aggregation and analgesic activities^{[1, 2]}. Piperlongumine directly binds to and inhibits the antioxidant enzyme glutathione S-transferase Pi 1, leading to increased ROS levels in cancer cells and inducing cell apoptosis, while having no obvious toxicity to normal cells^[3].

In vitro, treatment of leukemia U937 cells with Piperlongumine (0-20µM) for 48h inhibited cell proliferation in a time- and dose-dependent manner, induced cell apoptosis, increased the expression of intracellular anti-microtubule-associated protein 1A/1B-light chain 3 (LC3-I), and reduced the intracellular protein kinase B (Akt) level^[4]. Piperlongumine (0-20µM) treatment of prostate cancer PC-3 cells, breast cancer MCF-7 cells and renal cancer 786-O cells induced cell autophagy, reduced the phosphorylation levels of intracellular Akt effectors, GSK-3β and TSC2, and led to increased intracellular ROS production^[5]. Piperlongumine (0-5µM) treatment of thyroid cancer cell lines (IHH-4, WRO, 8505c and KMH-2 cells) for 24h and 48h inhibited the growth of all cells in a dose- and time-dependent manner, significantly reduced colony formation, and induced G2/M phase arrest and apoptosis^[6].

In vivo, Piperlongumine (10mg/kg) was treated by intraperitoneal injection in BxPC-3 cell xenograft mice for 24 days, which significantly inhibited tumor growth, reduced microvascular density in pancreatic tumor tissues and induced cell apoptosis, and eliminated the increase in NF-κB activity in pancreatic tumor tissues induced by Gemcitabine^[7]. Piperlongumine (50mg/kg/day) was treated orally in aged mice for 8 weeks, which significantly improved the novel object recognition and nesting behavior of aged mice, and increased the levels of calmodulin-dependent protein kinase IIα (CaMKIIα) and extracellular signal-regulated kinase 1/2 (ERK1/2) in the hippocampus^[8].

References:
[1] Piska K, Gunia-Krzyżak A, Koczurkiewicz P, et al. Piperlongumine (piplartine) as a lead compound for anticancer agents–Synthesis and properties of analogues: A mini-review[J]. European journal of medicinal chemistry, 2018, 156: 13-20.
[2] Martha Perez Gutierrez R, Maria Neira Gonzalez A, Hoyo-Vadillo C. Alkaloids from piper: a review of its phytochemistry and pharmacology[J]. Mini Reviews in Medicinal Chemistry, 2013, 13(2): 163-193.
[3] Chen Y J, Kuo C C, Ting L L, et al. Piperlongumine inhibits cancer stem cell properties and regulates multiple malignant phenotypes in oral cancer[J]. Oncology letters, 2018, 15(2): 1789-1798.
[4] Wang H, Wang Y, Gao H, et al. Piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways[J]. Oncology Letters, 2018, 15(2): 1423-1428.
[5] Makhov P, Golovine K, Teper E, et al. Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death[J]. British journal of cancer, 2014, 110(4): 899-907.
[6] Kung F P, Lim Y P, Chao W Y, et al. Piperlongumine, a potent anticancer phytotherapeutic, induces cell cycle arrest and apoptosis in vitro and in vivo through the ROS/Akt pathway in human thyroid cancer cells[J]. Cancers, 2021, 13(17): 4266.
[7] Wang Y, Wu X, Zhou Y, et al. Piperlongumine suppresses growth and sensitizes pancreatic tumors to gemcitabine in a xenograft mouse model by modulating the NF-kappa B pathway[J]. Cancer Prevention Research, 2016, 9(3): 234-244.
[8] Go J, Park T S, Han G H, et al. Piperlongumine decreases cognitive impairment and improves hippocampal function in aged mice[J]. International Journal of Molecular Medicine, 2018, 42(4): 1875-1884.

Piperlongumine是从Piper longum L.中提取的天然生物碱化合物，具有多种药理活性，包括抗肿瘤、脂质代谢调节、抗血小板聚集和镇痛活性等^{[1, 2]}。Piperlongumine直接结合并抑制抗氧化酶谷胱甘肽S-转移酶Pi 1，导致癌细胞内ROS水平升高，诱导细胞凋亡，而对正常细胞没有明显毒性^[3]。

在体外，Piperlongumine（0-20µM）处理白血病U937细胞48h，以时间和剂量依赖性方式抑制了细胞增殖，诱导了细胞凋亡，增加了细胞内抗微管相关蛋白 1A/1B-light链3（LC3-I）的表达，降低了细胞内蛋白激酶B（Akt）水平^[4]。Piperlongumine（0-20µM）处理前列腺癌PC-3细胞、乳腺癌MCF-7细胞和肾癌786-O细胞，诱导了细胞自噬，降低了细胞内Akt效应器、GSK-3β和TSC2的磷酸化水平，导致了细胞内ROS产生增加^[5]。Piperlongumine（0-5µM）处理甲状腺癌细胞系（IHH-4、WRO、8505c和KMH-2细胞）24h和48h，以剂量和时间依赖性方式抑制了所有细胞生长，显著减少了集落形成，诱导G2/M 期停滞和细胞凋亡^[6]。

在体内，Piperlongumine（10mg/kg）通过腹腔注射治疗BxPC-3细胞异种移植小鼠24天，显著抑制了肿瘤的生长，降低了胰腺肿瘤组织中的微血管密度并诱导细胞凋亡，消除了吉西他滨诱导的胰腺肿瘤组织中NF-κB活性的升高^[7]。Piperlongumine（50mg/kg/day）通过口服治疗老年小鼠8周，显著改善了老年小鼠的新物体识别和筑巢行为，增加了海马体中钙调蛋白依赖性蛋白激酶IIα（CaMKIIα）和细胞外信号调节激酶1/2（ERK1/2）的水平^[8]。