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Expert Opinion on Therapeutic Targets 2023Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity.... (Review)
Review
INTRODUCTION
Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy.
AREAS COVERED
Triphenylphosphonium cation (TPP)-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP-based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies.
EXPERT OPINION
TPP-based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP-based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP-based OXPHOS-inhibiting drugs in cancer prevention and treatment.
Topics: Humans; Mice; Animals; Mitochondria; Oxidative Phosphorylation; Neoplasms; Drug Delivery Systems; Antineoplastic Agents
PubMed: 37736880
DOI: 10.1080/14728222.2023.2261631 -
ACS Pharmacology & Translational Science May 2024CDK5 kinase plays a central role in the regulation of neuronal functions, and its hyperactivation has been associated with neurodegenerative pathologies and more...
CDK5 kinase plays a central role in the regulation of neuronal functions, and its hyperactivation has been associated with neurodegenerative pathologies and more recently with several human cancers, in particular lung cancer. However, ATP-competitive inhibitors targeting CDK5 are poorly selective and suffer limitations, calling for new classes of inhibitors. In a screen for allosteric modulators of CDK5, we identified ethaverine and closely related derivative papaverine and showed that they inhibit cell proliferation and migration of non small cell lung cancer cell lines. Moreover the efficacy of these compounds is significantly enhanced when combined with the ATP-competitive inhibitor roscovitine, suggesting an additive dual mechanism of inhibition targeting CDK5. These compounds do not affect CDK5 stability, but thermodenaturation studies performed with A549 cell extracts infer that they interact with CDK5 . Furthermore, the inhibitory potentials of ethaverine and papaverine are reduced in A549 cells treated with siRNA directed against CDK5. Taken together, our results provide unexpected and novel evidence that ethaverine and papaverine constitute promising leads that can be repurposed for targeting CDK5 in lung cancer.
PubMed: 38751642
DOI: 10.1021/acsptsci.4c00023 -
Journal of Vascular Surgery Cases and... Dec 2023We present a case of medication-induced priapism that was refractory to conventional urologic methods and required treatment with a caverno-saphenous bypass. The patient...
We present a case of medication-induced priapism that was refractory to conventional urologic methods and required treatment with a caverno-saphenous bypass. The patient had been misusing an injectable erectile dysfunction medication consisting of alprostadil, papaverine, and phentolamine (Trimix), resulting in multiple episodes of priapism. His initial episodes of priapism were successfully treated with the traditional urologic algorithm, including phenylephrine, aspiration, and distal shunting. However, due to his continued medication misuse, these became ineffective, requiring proximal shunt surgery. Priapism requiring an extra-anatomic bypass is exceedingly rare. Following our proximal shunt surgery, he maintained partial sexual function, and his bypass remained patent.
PubMed: 38106342
DOI: 10.1016/j.jvscit.2023.101359 -
Joint Diseases and Related Surgery Apr 2024The study aimed to examine the histopathological and biomechanical effects of papaverine administered intraperitoneally and locally on Achilles tendon healing in a rat...
OBJECTIVES
The study aimed to examine the histopathological and biomechanical effects of papaverine administered intraperitoneally and locally on Achilles tendon healing in a rat model.
MATERIALS AND METHODS
Forty-eight adult male Sprague-Dawley rats (range, 300 to 400 g) were used in this study conducted between October and November 2022. The rats were divided into three groups, with each group further subdivided into two for sacrifice on either the 15 (early period) or 30 (late period) day after surgery. The first (control) group received no treatment following Achilles tendon repair, while papaverine was intraperitoneally administered every other day for 10 days in the second group and locally in the third group after surgery. On the 15 and 30 days, the rats were sacrificed, and their Achilles tendons were subjected to biomechanical testing and histopathological evaluation.
RESULTS
Histopathologically, there were no significant differences among the groups on the 15 day. However, on the 30 day, the locally applied papaverine group exhibited superior histopathological outcomes compared to the control group (p<0.05). Concerning the highest tensile strength values before rupture, the biomechanical assessment showed that the group receiving local papaverine treatment in the early period and both the group with systemic papaverine treatment and the one with local papaverine treatment in the late period displayed a statistically significant advantage compared to the control group (p<0.05).
CONCLUSION
Locally administered papaverine has positive biomechanical effects in the early period and exhibits a positive correlation both histopathologically and biomechanically in the late period. Novel therapeutic options may be provided for patients through these findings.
Topics: Animals; Achilles Tendon; Papaverine; Rats, Sprague-Dawley; Male; Tissue Adhesions; Wound Healing; Tendon Injuries; Rats; Tensile Strength; Injections, Intraperitoneal; Biomechanical Phenomena; Disease Models, Animal
PubMed: 38727117
DOI: 10.52312/jdrs.2024.1656 -
Journal of Ethnopharmacology Dec 2023Rosa webbiana (Family: Rosaceae) is used by South Asian herbalists to treat gastrointestinal and respiratory disorders.
Ethnopharmacological basis and pharmacodynamics prospectives for folkloric claims of Rosa webbiana wall. Ex. Royle in diarrhea and asthma via In vitro, In vivo and In silico techniques.
ETHNOPHARMACOLOGICAL RELEVANCE
Rosa webbiana (Family: Rosaceae) is used by South Asian herbalists to treat gastrointestinal and respiratory disorders.
AIM OF THE STUDY
This research aimed at multiple targets to verify R. webbiana for treating diarrhea and asthma. In vitro, in vivo, and in silico experiments were planned to demonstrate the antispasmodic and bronchodilator potential of R. webbiana.
MATERIALS AND METHODS
The bioactive compounds of R. webbiana were identified and quantified through LC ESI-MS/MS and HPLC. These compounds were predicted for muti-mechanisms of bronchodilator and antispasmodic potential in network pharmacology and molecular docking. In vitro methods (isolated rabbit trachea, bladder, and jejunum tissues) confirmed these multi-mechanisms for antispasmodic and bronchodilator effects. Antiperistalsis, antidiarrheal, and antisecretory experiments were conducted in in-vivo experiments.
RESULTS
The phytochemical analysis indicates the presence of rutin (742.91 μg/g), kaempferol (726.32 μg/g), and quercitrin (688.20 μg/g) in Rw. EtOH. These bioactive compounds in network pharmacology interfere with the pathogenic genes of diarrhea and asthma, which are the members of calcium-mediated signaling pathways and showed the stronger binding affinity towards voltage-gated L-type calcium channels, myosin light chain-kinase, Calcium calmodulin-dependent-kinase, Phosphodiesterase-4, and phosphoinositide phospholipase-C in molecular docking. Rw. EtOH elicited a spasmolytic response in isolated jejunum, trachea, and urine preparations by relaxing K (80 mM) and CCh (1 μM) spastic contractions. Additionally, it suppressed calcium concentration-response curves to the right, like verapamil. Like dicyclomine, it caused a rightward parallel shift of the CCh curves, followed by a non-parallel shift at higher concentrations with suppression of the maximal response. Like papaverine, it also caused isoprenaline-induced inhibitory CRCs to shift to the left. Verapamil did not potentiate isoprenaline-induced inhibitory CRCs, although it was more efficacious against K (80 mM) than CCh (1 μM)-induced contractions. R. webbiana EtOH extract exhibited complete antiperistalsis (21.55%), antidiarrheal (80.33%), and antisecretory (82.59±0.60) activities in vivo experiments at the dose of 300 mg/kg.
CONCLUSION
Thus, Rw. EtOH modulated multiple pathways, produced calcium antagonistic, anticholinergic, and phosphodiesterase inhibitory actions, and had antidiarrheal and bronchodilator effects.
Topics: Animals; Rabbits; Antidiarrheals; Parasympatholytics; Bronchodilator Agents; Rosa; Isoproterenol; Molecular Docking Simulation; Calcium; Prospective Studies; Tandem Mass Spectrometry; Plant Extracts; Diarrhea; Verapamil; Jejunum; Gastrointestinal Agents; Calcium Channels; Asthma
PubMed: 37315649
DOI: 10.1016/j.jep.2023.116696 -
American Journal of Obstetrics &... May 2024Catheter-balloon insertion is a cervical ripening method of labor induction. Papaverine and its derivatives are musculotropic antispasmodic drugs that directly induce...
BACKGROUND
Catheter-balloon insertion is a cervical ripening method of labor induction. Papaverine and its derivatives are musculotropic antispasmodic drugs that directly induce smooth muscle relaxation. Used during childbirth, these drugs have been suggested to shorten the duration of labor.
OBJECTIVE
We aimed to evaluate the effect of administering papaverine prior to catheter-balloon insertion on changes in Bishop-scores and on the induction-to-delivery interval.
STUDY DESIGN
This randomized double-blinded placebo-controlled trial was conducted in a single tertiary university-affiliated hospital. Participants were admitted at term for labor induction with an initial Bishop-score ≤6. Participants were randomized to receive papaverine intravenous 80 mg or saline 0.9%, within 30 minutes of Foley catheter-balloon insertion. The co-primary outcomes were the difference in Bishop-score from before catheter-balloon insertion to after removal, and the induction-to-delivery interval. Secondary outcomes included maternal pain and satisfaction-scores, delivery within 24-hours and neonatal outcome. Both intention-to-treat analysis and per protocol analysis were performed.
RESULTS
In total, 110 women were enrolled. In the intention-to-treat analysis, for the papaverine (N=55) compared to the placebo group (N=55), the median (range) difference in Bishop-score was greater: 7 (range, 4-11) vs. 6 (1-11), p=0.023; and the median range catheter insertion-to-delivery interval was shorter: 21(6-95) vs. 26 (3-108) hours, p=0.031. A higher proportion of women in the papaverine than placebo group delivered within 24-hours: 65.5% vs. 41.8%, p=0.012. Pain and satisfaction-scores, delivery and neonatal outcomes were similar between the groups. Similar results were found in the per protocol analysis.
CONCLUSIONS
Papaverine prior to Foley-catheter insertion for cervical ripening resulted in improved Bishop-scores and shorter catheter-to-delivery intervals.
PubMed: 38825005
DOI: 10.1016/j.ajogmf.2024.101388 -
Huan Jing Ke Xue= Huanjing Kexue May 2024It is a new approach to identify legal or illegal use of morphine through information on municipal wastewater. However, the sources of morphine in wastewater are...
It is a new approach to identify legal or illegal use of morphine through information on municipal wastewater. However, the sources of morphine in wastewater are complex, and distinguishing the contribution of different sources has become a key issue. A total of 262 influent samples from 61 representative wastewater treatment plants in a typical city were collected from October 2022 to March 2023. The concentrations of morphine, codeine, thebaine, papaverine, noscapine, and monoacetylmorphine were analyzed in wastewater and poppy straws. Combined with the proportion of alkaloids in poppy straws, the source analysis of alkaloids in wastewater was analyzed using the ratio method and positive matrix factorization model (PMF). Only five alkaloids were detected in wastewater, and monoacetylmorphine, a metabolite of heroin, was not detected. The concentrations of morphine and codeine were significantly higher than those of noscapine, papaverine, and thebaine. By constructing the ratios of codeine/(morphine + codeine) and noscapine/(noscapine + codeine), the source of poppy straw could be qualitatively distinguished. The PMF results showed that three sources of morphine for medical use, poppy straw, and codeine contributed 44.9%, 43.7%, and 9.4%, respectively. The different sources varied in these months due to the COVID-19 and influenza A outbreaks, in which the use of drugs containing poppy straws and codeine was the main source, whereas the use of morphine analgesics remained relatively stable. Inventory analysis further demonstrated the reliability of the source contributions from the PMF model, and morphine was not abused in this city.
Topics: Morphine; Wastewater; Papaverine; Thebaine; Noscapine; Reproducibility of Results; Codeine; Morphine Derivatives; Alkaloids; Papaver
PubMed: 38629538
DOI: 10.13227/j.hjkx.202306005 -
Molecules (Basel, Switzerland) Apr 2024Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether...
Unraveling the Nephroprotective Potential of Papaverine against Cisplatin Toxicity through Mitigating Oxidative Stress and Inflammation: Insights from In Silico, In Vitro, and In Vivo Investigations.
Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether papaverine could mitigate cisplatin-induced kidney damage while preserving its chemotherapeutic efficacy. Integrative bioinformatics analysis predicted papaverine modulation of the mechanistic pathways related to cisplatin renal toxicity; notably, mitogen-activated protein kinase 1 (MAPK1) signaling. We validated protective effects in normal kidney cells without interfering with cisplatin cytotoxicity on a cancer cell line. Concurrent in vivo administration of papaverine alongside cisplatin in rats prevented elevations in nephrotoxicity markers, including serum creatinine, blood urea nitrogen, and renal oxidative stress markers (malondialdehyde, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines), as tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6). Papaverine also reduced apoptosis markers such as Bcl2 and Bcl-2-associated X protein (Bax) and kidney injury molecule-1 (KIM-1), and histological damage. In addition, it upregulates antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) while boosting anti-inflammatory signaling interleukin-10 (IL-10). These effects were underlined by the ability of Papaverine to downregulate MAPK-1 expression. Overall, these findings show papaverine could protect against cisplatin kidney damage without reducing its cytotoxic activity. Further research would allow the transition of these results to clinical practice.
Topics: Cisplatin; Papaverine; Oxidative Stress; Animals; Rats; Inflammation; Humans; Kidney; Male; Apoptosis; Antineoplastic Agents; Protective Agents; Antioxidants; Cytokines; Computer Simulation; Biomarkers
PubMed: 38731418
DOI: 10.3390/molecules29091927