Inducing Cytotoxicity in Colon Cancer Cells and Suppressing Cancer Stem Cells by Dolasetron and Ketoprofen through Inhibition of RNA Binding Protein PUM1.

Clinical trials of new drugs often face a high failure rate of approximately 45 percent due to safety and toxicity concerns. Repurposing drugs with well-established safety profiles becomes crucial in addressing this challenge. Colon cancer ranks as the third most prevalent cancer and the second leading cause of cancer related mortality worldwide. This study focuses on the RNA-binding protein pumilio1 (PUM1), a member of the PUF family involved in post-transcriptional gene expression regulation. By utilizing molecular docking techniques and FDA-approved drugs, potential inhibitors against PUM1 were identified. Notably, dolasetron and ketoprofen demonstrated promising results, exhibiting strong binding affinity, hydrophobic interactions, and favorable chemical reactivity according to Conceptual-DFT calculations. Both compounds effectively reduced cell viability, with IC50 values of 150 µM and 175 µM, respectively and shows long term inhibitory effects as seen by reduced in number of colonies. Moreover, they exhibited inhibitory effects on colon cancer stem cells, as indicated by reduced colonospheroid size and numbers. Apoptosis is induced by these compounds and has triggered activation of executioner caspase 3/7 in HCT116 cells which is evident through a caspase 3/7 assay and AO/EB staining, while the non-toxic effect of these compounds was evident from viability against non-cancerous cell line and hemolysis assay. Additionally, the treatment group showed a significant decrease in PUM1 and cancer stem cell markers expression compared to the control group. In conclusion, this study highlights the potential of targeting PUM1 as a novel approach to colon cancer treatment. Dolasetron and ketoprofen demonstrate promise as effective anti-cancer and anti-cancer stem cell drugs, inducing apoptosis in colon cancer cells through inhibition of PUM1.

Establishment and application of DUE criteria of Dolasetron / 药学实践杂志

Objective To establish the drug use evaluation ( DUE) of Dolasetron, evaluate the rationality of the clinical use of Dolasetron and provide a reference for the rationally clinical use of Dolasetron．Methods On the basis of Dolasetron DUE criteria, a retrospective analysis was made in 794 hospitalized patients from January 2021 to June 2021. Results The drug use evaluation criterion on Dolasetron consisted of drug indications, drug use process, the result of drug use and indication management. Conclusion There are some inappropriate medication problems in Dolasetron utilization in the hospital. The DUE criterion is very practical which could be used to standardize the clinical utilization of Dolasetron.

Synthesis and Development of Indole Based 5-HT3 Receptor Antagonists as Anti-Emetic Drugs in Oncology: An Update.

An important group of antiemetic drugs used in the treatment of nausea and vomiting after chemotherapy containing an indole moiety in their structures, working as 5- hydroxytryptamine type 3 serotonin receptor antagonist (5-HT3). This study focuses on compounds bearing an indole core that present a 5-HT3 receptor antagonist activity, which have been successfully used as antiemetic drugs for reducing chemotherapy adverse secondary effects during cancer treatment. Their synthesis, biological activities, and some outstanding characteristics are discussed, providing a general outlook towards the development of more efficient antiemetic drugs.

CdS nanocrystals as fluorescent probe for detection of dolasetron mesylate in aqueous solution: Application to biomedical analysis.

A simple and straightforward method for the determination of dolasetron mesylate (DM) in aqueous solution was developed based on the fluorescence quenching of 3-Mercaptopropionic acid (MPA) capped CdS quantum dots (QDs). The structure, morphology, and optical properties of synthesized QDs were characterized by using UV-Vis absorption spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements. Under the optimum conditions, the MPA-CdS QDs fluorescence probe offered good sensitivity and selectivity for detecting DM. The probe provided a highly specific selectivity and a linear detection of DM in the range of 2-40 µg/mL with detection limit (LOD) 1.512 µg/mL. The common excipients did not interfere in the proposed method. The fluorescence quenching mechanism of CdS QDs is also discussed. The developed sensor was applied to the quantification of DM in urine and human serum sample with satisfactory results.

CdS nanocrystals as fluorescent probe for detection of dolasetron mesylate in aqueous solution:Application to biomedical analysis / 药物分析学报

A simple and straightforward method for the determination of dolasetron mesylate (DM) in aqueous solution was developed based on the fluorescence quenching of 3-Mercaptopropionic acid (MPA) capped CdS quantum dots (QDs). The structure, morphology, and optical properties of synthesized QDs were characterized by using UV-Vis absorption spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements. Under the optimum conditions, the MPA-CdS QDs fluorescence probe offered good sensitivity and selectivity for detecting DM. The probe provided a highly specific selectivity and a linear detection of DM in the range of 2–40 μg/mL with detection limit (LOD) 1.512 μg/mL. The common excipients did not interfere in the proposed method. The fluorescence quenching mechanism of CdS QDs is also discussed. The developed sensor was applied to the quantification of DM in urine and human serum sample with satisfactory results.

Molecular mechanisms of 5-HT(3) and NK(1) receptor antagonists in prevention of emesis.

Nausea and vomiting are major side effects of chemotherapy and one key reason for non-compliance with cancer treatment. The introduction of 5-HT3 receptor antagonists in the 1990s was a major advance in the prevention of acute emesis, and highlighted the critical role of serotonin in the emetic response. The next major advance in the treatment of chemotherapy induced nausea and vomiting (CINV) occurred in 2003 with the introduction of aprepitant, a tachykinin 1 (NK1) receptor antagonist. Aprepitant not only reduced acute emesis but also helped in the reduction of delayed emesis. Also in 2003, palonosetron, a second generation 5-HT3 receptor antagonist became available. Unlike the first generation 5-HT3 receptor antagonists, palonosetron demonstrated efficacy in preventing both acute and delayed emesis. This review focuses on the mechanism of action of 5-HT3 and NK1 receptor antagonists in acute and delayed CINV prevention. We discuss first, the medicinal chemistry that led to the discovery of these antagonists to underline their common structural features. Second, we discuss their performance in the clinic and what it tells us about the emetic response. Finally, we present recent mechanistic studies that help provide a rationale for efficacy differences between palonosetron and other 5-HT3 receptor antagonists in the clinic. In vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT3 receptor. The crossroads of acute and delayed emesis seem to include interactions among the 5-HT3 and NK1 receptor signaling pathways and inhibitions of these interactions could lead to improved treatment of CINV.

Reappraisal of the role of dolasetron in prevention and treatment of nausea and vomiting associated with surgery or chemotherapy.

Chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting are one of the most frequent but also very concerning consequences for patients undergoing chemotherapy or surgical procedures under general anesthesia. There are a variety of mechanisms involved in the activation of nausea and vomiting. Serotonin, a ubiquitous central and peripheral neurotransmitter, is thought to be the predominant mediator of the perception of nausea and triggering of the vomiting response in both the brain and the periphery via the 5-hydroxytryptamine type 3 (5-HT(3)) receptor pathways. 5-HT(3) receptor antagonists disrupt this pathway, largely at the level of the vagal afferent pathways, to decrease nausea and vomiting. This review will focus on dolasetron, an older but sill commonly used 5-HT(3) receptor antagonist and its multimodal mechanism of action, safety and tolerability, patient considerations, and a review of the current literature on its use to combat both chemotherapy-induced and postoperative nausea and vomiting in these two important patient populations.

The effects of prophylactic dolasetron and induction with propofol on postoperative nausea and vomiting after thyroidectomy.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common problem in patients undergoing thyroidectomy. In this study we evaluated the effects of prophylactic dolasetron and/or induction with propofol on PONV. METHODS: Two hundred three patients scheduled thyroidectomy under general anesthesia with sevoflurane were included and were randomly allocated to one of four groups. In control (group C) and dolasetron groups (group D), the patients received thiopental sodium 4-5 mg/kg intravenously for the induction of anesthesia, and the patients in group D received prophylactic intravenous dolasetron 210 microgram/kg. In propofol (group P) and dolasetron + propofol groups (group D + P), the patients received propofol 2 mg/kg intravenously for the induction of anesthesia, and the patients in group D + P received prophylactic intravenous dolasetron 210 microgram/kg. The incidence and severity of PONV, the need for rescue antiemetics, adverse events were assessed during 0 to 1 hour and 1 to 24 hours postoperatively. RESULTS: During the first 24 hours after anesthesia, the incidences of PONV and postoperative vomiting were significantly reduced in group D + P compared with group C (P < 0.05, respectively). There were no significant differences in postoperative nausea, need for rescue antiemetics, severity of PONV, and adverse events of antiemetics among the four groups. CONCLUSIONS: In patients with thyroidectomy, combination of prophylactic dolasetron administration and induction with propofol was found to reduce the incidence of PONV during the first 24 hours after anesthesia, compared with that of routine induction with thiopental sodium.

The effects of prophylactic dolasetron and induction with propofol on postoperative nausea and vomiting after thyroidectomy / 대한마취과학회지

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common problem in patients undergoing thyroidectomy. In this study we evaluated the effects of prophylactic dolasetron and/or induction with propofol on PONV. METHODS: Two hundred three patients scheduled thyroidectomy under general anesthesia with sevoflurane were included and were randomly allocated to one of four groups. In control (group C) and dolasetron groups (group D), the patients received thiopental sodium 4-5 mg/kg intravenously for the induction of anesthesia, and the patients in group D received prophylactic intravenous dolasetron 210 microgram/kg. In propofol (group P) and dolasetron + propofol groups (group D + P), the patients received propofol 2 mg/kg intravenously for the induction of anesthesia, and the patients in group D + P received prophylactic intravenous dolasetron 210 microgram/kg. The incidence and severity of PONV, the need for rescue antiemetics, adverse events were assessed during 0 to 1 hour and 1 to 24 hours postoperatively. RESULTS: During the first 24 hours after anesthesia, the incidences of PONV and postoperative vomiting were significantly reduced in group D + P compared with group C (P < 0.05, respectively). There were no significant differences in postoperative nausea, need for rescue antiemetics, severity of PONV, and adverse events of antiemetics among the four groups. CONCLUSIONS: In patients with thyroidectomy, combination of prophylactic dolasetron administration and induction with propofol was found to reduce the incidence of PONV during the first 24 hours after anesthesia, compared with that of routine induction with thiopental sodium.

The Effect of Ondansetron or Dolasetron for the Prevention of Postoperative Nausea and Vomiting in Patients with Intravenous Patient-controlled Analgesia / 대한마취과학회지

BACKGROUND: Postoperative nausea and vomiting (PONV) are common problems in patients undergoing breast surgery or with intravenous patient-controlled analgesia (IV PCA). We evaluated the effect of ondansetron or dolasetron for the prevention of PONV in patients undergoing a mastectomy with IV PCA. METHODS: A total of 126 patients were randomly divided into three groups. The PCA group was a control group. For the PCAO group (IV PCA mixed with ondanseron), 4 mg ondansetron was intravenously injected 30 min before the end of surgery and 8 mg was mixed in IV PCA. For the PCAD group (IV PCA mixed with dolasetron), 10 mg dolasetron and 20 mg was administered as same manner with the PCAO group. The incidence of PONV, the need for rescue antiemetics, adverse events, and the nausea and vomiting severity score were analyzed for 1 hour and 24 hours postoperative periods. RESULTS: During the first 24 hours postoperatively, the incidence of PONV was 76.2% for the PCA group, 70.7% for the PCAO group (P > 0.05 versus the PCA group) and 66.7% for the PCAD group (P > 0.05 versus the PCA group), respectively. The incidence of need for rescue antiemetics was 40.5% for the PCA group, 9.5% for the PCAO group (P < 0.05 versus the PCA group) and 4.8% for the PCAD group (P < 0.05 versus the PCA group), respectively. CONCLUSIONS: In the patients receiving IV PCA after a mastectomy, ondansetron or dolasetron were not effective for the reduction of the incidence of PONV. However, the need for rescue antiemetics was significantly decreased.

Determination of Dolasetron Mesylate by HPLC / 中国药房

OBJECTIVE:To establish a HPLC method for the determination of dolastron mesylate.METHODS:The sample was separated on Diamonsil C18 column.The mobile phase consisted of acetonitrile-water-1mol? L-1 ammonium formate(450∶ 440∶ 110)(pH=8.0 adjusted with trithylamine)with a flow rate of 1.0mL? min-1.The UV detection wavelength was set at 285nm and the sample size was 20? L.RESULTS:The linear range of dolasetron mesylate was 24～ 56? g? min-1(r=0.999 6),with average recovery at 99.7%(RSD=0.74%).CONCLUSION:The established is simple,sensitive and reproducible,and suitable for the quality control of dolasetron mesylate.

Open-label, randomized comparison of the efficacy of intravenous dolasetron mesylate and ondansetron in the prevention of acute and delayed cisplatin-induced emesis in cancer patients.

PURPOSE: The aim of this study is to compare the antiemetic efficacy and tolerability of intravenous dolasetron mesylate and ondansetron in the prevention of acute and delayed emesis. MATERIAL AND METHODS: From April 2002 through October 2002, a total of 112 patients receiving cisplatin- based combination chemotherapy were randomized to receive a single i.v. dose of dolasetron 100 mg or ondansetron 8 mg, 30 minutes before the initiation of chemotherapy. In the ondansetron group, two additional doses of ondansetron 8 mg were given at intervals of 2 to 4 hours. To prevent delayed emesis, dolasetron 200 mg p.o. daily or ondansetron 8 mg p.o. bid was administered from the 2(nd) days to a maximum of 5 days. The primary end point was the proportion of patients that experienced no emetic episodes and required no rescue medication (complete response, CR) during the 24 hours (acute period) and during Day 2 to Day 5+/-2 days (delayed period), after chemotherapy. The secondary end points included the incidence and severity of emesis. RESULTS: 105 patients were evaluable for efficacy. CR rates during the acute period were 36.0% for a single dose of dolasetron 100 mg, and 43.6% for three doses of ondansetron 8 mg. CR rates during the delayed period were 8.0% and 10.9%, respectively. There was no significant difference in the efficacy between the two groups. Adverse effects were mostly mild to moderate and not related to study medication. CONCLUSIONS: A single i.v. dose of dolasetron 100 mg is as effective as three i.v. doses of ondansetron 8 mg in preventing acute and delayed emesis after cisplatin-based chemotherapy, with a comparable safety profile.

Open-label, Randomized Comparison of the Efficacy of Intravenous Dolasetron Mesylate and Ondansetron in the Prevention of Acute and Delayed Cisplatin-induced Emesis in Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The aim of this study is to compare the antiemetic efficacy and tolerability of intravenous dolasetron mesylate and ondansetron in the prevention of acute and delayed emesis. MATERIAL AND METHODS: From April 2002 through October 2002, a total of 112 patients receiving cisplatin- based combination chemotherapy were randomized to receive a single i.v. dose of dolasetron 100 mg or ondansetron 8 mg, 30 minutes before the initiation of chemotherapy. In the ondansetron group, two additional doses of ondansetron 8 mg were given at intervals of 2 to 4 hours. To prevent delayed emesis, dolasetron 200 mg p.o. daily or ondansetron 8 mg p.o. bid was administered from the 2nd days to a maximum of 5 days. The primary end point was the proportion of patients that experienced no emetic episodes and required no rescue medication (complete response, CR) during the 24 hours (acute period) and during Day 2 to Day 5 2 days (delayed period), after chemotherapy. The secondary end points included the incidence and severity of emesis. RESULTS: 105 patients were evaluable for efficacy. CR rates during the acute period were 36.0% for a single dose of dolasetron 100 mg, and 43.6% for three doses of ondansetron 8 mg. CR rates during the delayed period were 8.0% and 10.9%, respectively. There was no significant difference in the efficacy between the two groups. Adverse effects were mostly mild to moderate and not related to study medication. CONCLUSIONS: A single i.v. dose of dolasetron 100 mg is as effective as three i.v. doses of ondansetron 8 mg in preventing acute and delayed emesis after cisplatin- based chemotherapy, with a comparable safety profile.