PMID- 35444553
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231028
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 13
DP  - 2022
TI  - Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and 
      Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus 
      Against Diverse Emetogens in the Least Shrew (Cryptotis parva).
PG  - 848673
LID - 10.3389/fphar.2022.848673 [doi]
LID - 848673
AB  - 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 (p < 0.05 and p < 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 (p < 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(2/3) receptors (apomorphine and quinpirole); 2) serotonergic 5-HT(3) receptors 
      [5-HT (serotonin) and 2-methyl-5-HT]; 3) cholinergic M(1) receptors (pilocarpine 
      and McN-A-343); 4) substance P neurokinin NK(1) receptors (GR73632); 5) the 
      L-type calcium (Ca(2+)) channel (LTCC) (FPL64176); 6) the sarcoplasmic 
      endoplasmic reticulum Ca(2+) ATPase inhibitor, thapsigargin; 7) the CB(1) 
      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.
CI  - Copyright (c) 2022 Belkacemi, Sun and Darmani.
FAU - Belkacemi, Louiza
AU  - Belkacemi L
AD  - Department of Basic Medical Sciences, College of Osteopathic Medicine of the 
      Pacific, Western University of Health Sciences, Pomona, CA, United States.
FAU - Sun, Yina
AU  - Sun Y
AD  - Department of Basic Medical Sciences, College of Osteopathic Medicine of the 
      Pacific, Western University of Health Sciences, Pomona, CA, United States.
FAU - Darmani, Nissar A
AU  - Darmani NA
AD  - Department of Basic Medical Sciences, College of Osteopathic Medicine of the 
      Pacific, Western University of Health Sciences, Pomona, CA, United States.
LA  - eng
GR  - R01 CA207287/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20220404
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC9014009
OTO - NOTNLM
OT  - analogs
OT  - antiemetic
OT  - dorsal vagal complex
OT  - emesis
OT  - least shrew
OT  - nucleus tractus solitarius
OT  - temsirolimus
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/04/22 06:00
MHDA- 2022/04/22 06:01
PMCR- 2022/04/04
CRDT- 2022/04/21 05:43
PHST- 2022/01/04 00:00 [received]
PHST- 2022/03/04 00:00 [accepted]
PHST- 2022/04/21 05:43 [entrez]
PHST- 2022/04/22 06:00 [pubmed]
PHST- 2022/04/22 06:01 [medline]
PHST- 2022/04/04 00:00 [pmc-release]
AID - 848673 [pii]
AID - 10.3389/fphar.2022.848673 [doi]
PST - epublish
SO  - Front Pharmacol. 2022 Apr 4;13:848673. doi: 10.3389/fphar.2022.848673. 
      eCollection 2022.