Belkacemi Louiza, Sun Yina, Darmani Nissar A
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States.
Front Pharmacol. 2022 Apr 4;13:848673. doi: 10.3389/fphar.2022.848673. eCollection 2022.
Temsirolimus is a prodrug form of sirolimus (rapamycin). With its analogs (everolimus, ridaforolimus, and rapamycin), it forms a group of anticancer agents that block the activity of one of the two mammalian targets of rapamycin (mTOR) complexes, mTORC1. We investigated the emetic potential of varying doses (0, 0.5, 1, 2.5, 5, 10, 20, and 40 mg/kg, i.p.) of temsirolimus in the least shrew. Temsirolimus caused a bell-shaped and dose-dependent increase in both the mean vomit frequency and the number of shrews vomiting with maximal efficacy at 10 mg/kg ( < 0.05 and < 0.02, respectively). Its larger doses (20 or 40 mg/kg) had no significant emetic effect. We also evaluated the emetic potential of its analogs (5, 10, and 20 mg/kg, i.p.), all of which exhibited a similar emetic profile. Our observational studies indicated that temsirolimus can reduce the shrew motor activity at 40 mg/kg, and subsequently, we examined the motor effects of its lower doses. At 10 and 20 mg/kg, it did not affect the spontaneous locomotor activity (distance moved) but attenuated the mean rearing frequency in a U-shaped manner at 10 mg/kg ( < 0.05). We then determined the broad-spectrum antiemetic potential of a 20 mg/kg (i.p.) dose of temsirolimus against diverse emetogens, including selective and nonselective agonists of 1) dopaminergic D receptors (apomorphine and quinpirole); 2) serotonergic 5-HT receptors [5-HT (serotonin) and 2-methyl-5-HT]; 3) cholinergic M receptors (pilocarpine and McN-A-343); 4) substance P neurokinin NK receptors (GR73632); 5) the L-type calcium (Ca) channel (LTCC) (FPL64176); 6) the sarcoplasmic endoplasmic reticulum Ca ATPase inhibitor, thapsigargin; 7) the CB receptor inverse agonist/antagonist, SR141716A; and 8) the chemotherapeutic cisplatin. Temsirolimus prevented vomiting evoked by the aforementioned emetogens with varying degrees. The mechanisms underlying the pro- and antiemetic effects of temsirolimus evaluated by immunochemistry for c-fos expression demonstrated a c-fos induction in the AP and NTS, but not DMNX with the 10 mg/kg emetic dose of temsirolimus, whereas its larger antiemetic dose (20 mg/kg) had no significant effect. Our study is the first to provide preclinical evidence demonstrating the promising antiemetic potential of high doses of temsirolimus and possibly its analogs in least shrews.
替西罗莫司是西罗莫司（雷帕霉素）的前药形式。它与同类物（依维莫司、利达罗莫司和雷帕霉素）构成一组抗癌药物，可阻断雷帕霉素的两个哺乳动物靶点之一的mTOR复合物（mTORC1）的活性。我们研究了不同剂量（0、0.5、1、2.5、5、10、20和40mg/kg，腹腔注射）的替西罗莫司对最小的鼩鼱的催吐潜力。替西罗莫司导致平均呕吐频率和呕吐的鼩鼱数量呈钟形且剂量依赖性增加，在10mg/kg时效果最佳（分别为<0.05和<0.02）。其较大剂量（20或40mg/kg）没有显著的催吐作用。我们还评估了其同类物（5、10和20mg/kg，腹腔注射）的催吐潜力，它们都表现出相似的催吐特征。我们的观察性研究表明，替西罗莫司在40mg/kg时可降低鼩鼱的运动活性，随后，我们研究了其较低剂量的运动效应。在10和20mg/kg时，它不影响自发运动活性（移动距离），但在10mg/kg时以U形方式减弱平均竖毛频率（<0.05）。然后，我们确定了20mg/kg（腹腔注射）剂量的替西罗莫司对多种催吐剂的广谱止吐潜力，这些催吐剂包括：1）多巴胺能D受体的选择性和非选择性激动剂（阿扑吗啡和喹吡罗）；2）5-羟色胺能5-HT受体[5-HT（血清素）和2-甲基-5-HT]；3）胆碱能M受体（毛果芸香碱和McN-A-343）；4）P物质神经激肽NK受体（GR73632）；5）L型钙（Ca）通道（LTCC）（FPL64176）；6）肌浆内质网Ca ATP酶抑制剂毒胡萝卜素；7）CB受体反向激动剂/拮抗剂SR141716A；8）化疗药物顺铂。替西罗莫司不同程度地预防了上述催吐剂引起的呕吐。通过免疫化学评估替西罗莫司促吐和止吐作用的机制，发现10mg/kg催吐剂量的替西罗莫司可诱导AP和NTS中的c-fos表达，但不诱导DMNX中的c-fos表达，而其较大的止吐剂量（20mg/kg）没有显著影响。我们的研究首次提供了临床前证据，证明高剂量的替西罗莫司及其同类物在最小的鼩鼱中具有有前景的止吐潜力。
