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Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer.Cell Reports. Medicine Feb 2024Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of...
Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of docetaxel resistance constitutes a major clinical challenge. Here, we demonstrate activation of the cholinergic muscarinic M1 receptor (CHRM1) in CRPC cells upon acquiring resistance to docetaxel, which is manifested in tumor tissues from PC patients post- vs. pre-docetaxel. Genetic and pharmacological inactivation of CHRM1 restores the efficacy of docetaxel in resistant cells. Mechanistically, CHRM1, via its first and third extracellular loops, interacts with the SEMA domain of cMET and forms a heteroreceptor complex with cMET, stimulating a downstream mitogen-activated protein polykinase program to confer docetaxel resistance. Dicyclomine, a clinically available CHRM1-selective antagonist, reverts resistance and restricts the growth of multiple docetaxel-resistant CRPC cell lines and patient-derived xenografts. Our study reveals a CHRM1-dictated mechanism for docetaxel resistance and identifies a CHRM1-targeted combinatorial strategy for overcoming docetaxel resistance in PC.
Topics: Male; Humans; Docetaxel; Receptor, Muscarinic M1; Prostatic Neoplasms, Castration-Resistant; Cell Line, Tumor; Cholinergic Agents
PubMed: 38262412
DOI: 10.1016/j.xcrm.2023.101388 -
The Journal of Venomous Animals and... 2024The bioactive peptides derived from snake venoms of the Viperidae family species have been promising as therapeutic candidates for neuroprotection due to their ability...
Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (
BACKGROUND
The bioactive peptides derived from snake venoms of the Viperidae family species have been promising as therapeutic candidates for neuroprotection due to their ability to prevent neuronal cell loss, injury, and death. Therefore, this study aimed to evaluate the cytoprotective effects of a synthetic proline-rich oligopeptide 7a (PRO-7a;
METHODS
Both cells were pre-treated for four hours with different concentrations of PRO-7a, submitted to HO-induced damage for 20 h, and then the oxidative stress markers were analyzed. Also, two independent neuroprotective mechanisms were investigated: a) L-arginine metabolite generation via argininosuccinate synthetase (AsS) activity regulation to produce agmatine or polyamines with neuroprotective properties; b) M1 mAChR receptor subtype activation pathway to reduce oxidative stress and neuron injury.
RESULTS
PRO-7a was not cytoprotective in C6 cells, but potentiated the HO-induced damage to cell integrity at a concentration lower than 0.38 μM. However, PRO-7a at 1.56 µM, on the other hand, modified HO-induced toxicity in PC12 cells by restoring cell integrity, mitochondrial metabolism, ROS generation, and arginase indirect activity. The α-Methyl-DL-aspartic acid (MDLA) and L-N-Nitroarginine methyl ester (L-Name), specific inhibitors of AsS and nitric oxide synthase (NOS), which catalyzes the synthesis of polyamines and NO from L-arginine, did not suppress PRO-7a-mediated cytoprotection against oxidative stress. It suggested that its mechanism is independent of the production of L-arginine metabolites with neuroprotective properties by increased AsS activity. On the other hand, the neuroprotective effect of PRO-7a was blocked in the presence of dicyclomine hydrochloride (DCH), an M1 mAChR antagonist.
CONCLUSIONS
For the first time, this work provides evidence that PRO-7a-induced neuroprotection seems to be mediated through M1 mAChR activation in PC12 cells, which reduces oxidative stress independently of AsS activity and L-arginine bioavailability.
PubMed: 38362565
DOI: 10.1590/1678-9199-JVATITD-2023-0043 -
Saudi Pharmaceutical Journal : SPJ :... Apr 2024Total extract of () expressed potent bronchodilator effect in isolated Guinea pigs' tracheal muscles. Fractionation of total extract ( using liquid-liquid technique...
Total extract of () expressed potent bronchodilator effect in isolated Guinea pigs' tracheal muscles. Fractionation of total extract ( using liquid-liquid technique followed by bronchodilator testing indicated that the activity was trapped to the chloroform (CHCl) soluble fraction. Phytochemical study of the CHCl fraction guided by bronchodilator activity led to the isolation of 7 active flavones of which compounds (Tephroapollin G), (Acetyltephroapollin C), (4''-Dehydroxytephroapollin E), and (Tephroapollin F) were new. Structures were identified using relevant spectroscopic tools including optical rotations and CD data. Compounds , , and lanceolatin A () behaved like papaverine by inhibiting carbachol (CCh) as well as high potassium (K)-mediated contractions at equivalent concentrations with varied potencies whereas (-)-Tephroapollin G () selectively inhibited CCh-mediated contractions but was not found active against high K. -Tephroapollin F () and (-)-Pseudosemiglabrin () in contrast were significantly more potent to abolish CCh induced contraction when compared with high K similar to dicyclomine. Papaverine like dual phosphodiesterase enzyme Ca ion inhibitory activities of and were confirmed indirectly by the bolster of the isoprenaline curves against CCh to the left whereas Ca inhibitory effect of and - was confirmed by the rightward deflection of Ca concentration-response curves (CRCs) towards right with quashing of the maximum response in same fashion like verapamil. Moreover, compounds and at lower concentrations showed selective blockade of muscarinic receptor similar to atropine. Oral administration of the , CHCl and to guinea pigs significantly protected against bronchospasm induced by 0.2 % histamine aerosol .
PubMed: 38435847
DOI: 10.1016/j.jsps.2024.101992