Pharmacology Research & Perspectives

Investigation of the cytotoxicity induced by cannabinoids on human ovarian carcinoma cells

AbstractCannabinoids have been shown to induce anti‐tumor activity in a variety of carcinoma cells such as breast, prostate, and brain. The aim of the present study is to investigate the anti‐tumor activity of cannabinoids, CBD (cannbidiol), and CBG (cannabigerol) in ovarian carcinoma cells sensitive and resistant to chemotherapeutic drugs. Sensitive A2780 cells and resistant A2780/CP70 carcinoma cells and non‐carcinoma cells were exposed to varying concentrations of CBD, CBG, carboplatin or CB1 and CB2 receptor antagonists, AM251 and AM630, respectively, alone or in combination, at different exposure times and cytotoxicity was measured by MTT assay. The mechanism of action of CBD and CB in inducing cytotoxicity was investigated involving a variety of apoptotic and cell cycle assays. Treatment with CBD and CBG selectively, dose and time dependently reduced cell viability and induced apoptosis. The effect of CBD was stronger than CBG in all cell lines tested. Both CBD and CBG induced stronger cytotoxicity than afforded by carboplatin in resistant cells. The cytotoxicity induced by CBD was not CB1 or CB2 receptor dependent in both carcinoma cells, however, CBG‐induced cytotoxicity may involve CB1 receptor activity in cisplatin‐resistant carcinoma cells. A synergistic effect was observed when cannabinoids at sublethal doses were combined with carboplatin in both carcinoma cells. The apoptotic event may involve loss of mitochondrial membrane potential, Annexin V, caspase 3/7, ROS activities, and cell cycle arrest. Further studies are required to investigate whether these results are translatable in the clinic. Combination therapies with conventional cancer treatments using cannabinoids are suggested.

Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice

AbstractLenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β‐hydroxycortisol, deoxycholic acid, and 1β‐hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography–tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three‐compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.

Could cannabinoids provide a new hope for ovarian cancer patients?

AbstractIt is known that gynecological cancers remain a worldwide problem and as shown by the statistics, there is a need for new gynecological cancer treatments. Cannabinoids, the pharmacologically active compounds of the Cannabis sativa plant, have been used for many centuries by individuals as a symptomatic treatment to alleviate pain, nausea, vomiting, and to help stimulate appetite. Research has revealed that cannabinoids also exert anti‐cancer activity such as anti‐proliferative and pro‐apoptotic effects through a variety of mechanisms. There is significant value in the development of these compounds as anti‐cancer therapies in clinical practice as they do not produce the typical toxic side effects that exist with conventional therapies and recent clinical trials have shown their great tolerability by patients at high doses. Cannabinoids can induce psychoactive effects that could limit their progression. Therefore, non‐psychoactive cannabinoids are attracting pharmacological interest due to their inability to produce psychological effects. Recent studies have focussed on non‐psychoactive cannabinoids in ovarian cancer and have revealed promising pre‐clinical results that indicate that these compounds may have potential benefits in the treatment of these cancers. However, there are still unanswered questions and research gaps that need to be addressed. This review summarizes the current understanding of this topic and identifies the current gaps in knowledge that provide a useful direction for future work.

Morphine stimulates cervical cancer cells and alleviates cytotoxicity of chemotherapeutic drugs via opioid receptor‐dependent and ‐independent mechanisms

AbstractMorphine is frequently applied in cancer patients for pain management. However, its effects on cancer are not well understood but observed to be specific to certain cancer types. We previously revealed the stimulatory properties of morphine in esophageal carcinoma. This work addressed the effects of morphine and its underlying mechanisms in cervical cancer. Proliferation, apoptosis, and migration assays were performed to examine the effects of morphine alone and its combinatory effects with chemotherapeutic drugs. Immunoblotting and biochemical analysis were performed to determine the underlying mechanisms of morphine's action. Morphine promoted proliferation in opioid receptor‐dependent manner and stimulated migration in opioid receptor‐independent manner. However, morphine did not affect cervical cancer cell survival. Morphine also interfered with all tested chemotherapeutic drugs (e.g., cisplatin, 5‐FU, and paclitaxel) and alleviates their efficacy. Mechanistically, morphine‐stimulated growth via activating EGFR‐mediated signaling pathways and is opioid‐receptor‐dependent; morphine‐stimulated migration via activating RhoA‐mediated signaling pathways and this is opioid receptor‐independent. Our work suggests a strong correlation of this opioid receptor on growth factor signaling to stimulate growth and opioid receptor‐independent activation of RhoA and consequent migration. Our findings have the potential to guide the clinical use of morphine for patients with cervical cancer.