Therapeutic potential and molecular mechanisms of mycophenolic acid as an anticancer agent

Benjanuwattra, Juthipong; Chaiyawat, Parunya; Pruksakorn, Dumnoensun; Koonrungsesomboon, Nut

doi:10.1016/j.ejphar.2020.173580

Cited by 31 publications

(30 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Three derived compounds are described here. Mycophenolic acid is an extensively characterized drug with a range of cancer-relevant molecular targets and mechanisms 42 and asperphenamate is reported to be a cathepsin inhibitor 43 . By contrast, petrosamine B has not been widely studied although it has been reported to inhibit an enzyme from H. pylori 44 .…”

Section: Discussionmentioning

confidence: 99%

Identification of natural product modulators of Merkel cell carcinoma cell growth and survival

Smith

Hill

Gelb

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Merkel cell carcinoma (MCC) is a rare, but aggressive skin cancer the incidence of which has increased significantly in recent years. The majority of MCCs have incorporated Merkel cell polyomavirus (VP-MCC) while the remainder are virus-negative (VN-MCC). Although a variety of therapeutic options have shown promise in treating MCC, there remains a need for additional therapeutics as well as probes for better understanding MCC. A high-throughput screening campaign was used to assess the ability of > 25,000 synthetic and natural product compounds as well as > 20,000 natural product extracts to affect growth and survival of VN-MCC and VP-MCC cell lines. Sixteen active compounds were identified that have mechanisms of action reported in the literature along with a number of compounds with unknown mechanisms. Screening results with pure compounds suggest a range of potential targets for MCC including DNA damage, inhibition of DNA or protein synthesis, reactive oxygen species, and proteasome inhibition as well as NFκB inhibition while also suggesting the importance of zinc and/or copper binding. Many of the active compounds, particularly some of the natural products, have multiple reported targets suggesting that this strategy might be a particularly fruitful approach. Processing of several active natural product extracts resulted in the identification of additional MCC-active compounds. Based on these results, further investigations focused on natural products sources, particularly of fungal origin, are expected to yield further potentially useful modulators of MCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of natural product modulators of Merkel cell carcinoma cell growth and survival

Smith

Hill

Gelb

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…MPA AUC was also measured at 21 months in a 12-patient control group receiving triple therapy with CS showing a significant difference between the steroid-free and the steroid-treated groups at 21 months. Cyclosporine decreases the enterohepatic recycling of MPA by inhibiting the biliary excretion of the MPA metabolite MPA-7-O-glucuronide leading to reduced reabsorption of MPA from the gastrointestinal tract causing lower MPA exposure (Staatz and Tett 2007;Benjanuwattra, Pruksakorn, and Koonrungsesomboon 2020). Concurrent cyclosporine treatment could have influenced the MPA concentrations with higher cyclosporine concentrations causing lower MPA concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…MPA exposure may be affected by co-administration of other immunosuppressive agents, such as cyclosporine, which seems to decrease MPA AUC (Gaston et al, 2009;Pou et al, 2001;Benjanuwattra, Pruksakorn, and Koonrungsesomboon 2020). On the contrary tacrolimus has less effect on MMF pharmacokinetics (Kagaya et al, 2008;Van Gelder et al, 2001;Kim et al, 2018;Nashan et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Data regarding the influence of corticosteroids (CS) on MMF pharmacokinetics are limited and not uniform. CS could possibly increase hepatic clearance of MPA by induction of UDP-GT enzyme activity responsible for conversion of MPA to its inactive metabolite (Cattaneo et al, 2002;Staatz and Tett 2007;Rong et al, 2019;Benjanuwattra, Pruksakorn, and Koonrungsesomboon 2020). A prospective study on MPA exposure in combination with tacrolimus and CS found no change in MPA AUC after CS withdrawal (Kuypers et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of Corticosteroid Treatment on Mycophenolic Acid Exposure in Renal Transplant Patients—Results From the SAILOR Study

et al. 2021

View full text Add to dashboard Cite

Background: Mycophenolic acid (MPA) is a potent immunosuppressive agent used in solid organ transplantation. MPA exhibits large interindividual variation in dose-normalized plasma concentrations but is nevertheless usually prescribed as a fixed dose without use of therapeutic drug monitoring (TDM). Data on the effect of corticosteroid (CS) treatment on MPA concentrations during concomitant tacrolimus treatment remains sparse.Methods: Data is based on TDM of MPA area under the concentration curve (AUC) in 210 renal transplant recipients participating in the prospective, randomized, controlled, multi-center trial (SAILOR) where a steroid-free immunosuppressive regimen with mycophenolate mofetil (MMF) and low-dose tacrolimus was compared with a conventional prednisolone-based treatment regimen. Multilevel mixed-effects linear regression post-hoc analyses of MPA AUC was performed.Results: Median MPA AUC at baseline (within the first 2 weeks post-transplant) in patients taking 2 g MMF daily was 53 mg*h/L (interquartile range: 43–69 mg*h/L, min: 24—max: 117 mg*h/L). Between-patient variation in MPA AUC was up to 5-fold on the same MMF dose. Patients in the steroid-free group had 12.5% lower (95% CI; 3.2–20.9%, p = 0.01) MPA AUC levels at baseline compared to the steroid treated group. During follow-up (14 days–2 years post-transplant) there were no significant differences in MPA AUC between the groups with MPA AUC being 4.2% lower (95% CI: −4.8%−12,5%, p = 0.35) in the steroid-free vs standard treatment group in restricted analysis after multivariate adjustment for tacrolimus trough level, body weight, time after transplantation and MMF dose. MMF dose was positively correlated with MPA AUC (p < 0.001) whereas body weight was negatively correlated with MPA AUC (p < 0.001). MPA AUC was 0.4% (95% CI: 0.2–0.6%, p < 0.001) lower per 1 kg increase in weight. Tacrolimus trough levels had no significant effect on MPA AUC.Conclusion: Immunosuppression with CS during concomitant tacrolimus treatment was shortly after transplantation associated with a significantly higher MPA exposure but the effect was small and not maintained during follow-up. Low body weight was associated with higher MPA exposure, which suggests a potential for weight adjusted MMF dosing.

show abstract

“…Mycophenolate mofetil (MMF, Fig. 1 ) is a nonsteroidal immunosuppressive agent used in treating cancers ( Benjanuwattra et al, 2020 ; Ling et al, 2018 ), ocular inflammations ( Daniel et al, 2010 ), atopic dermatitis ( Grundmann-Kollmann et al, 2001 ), psoriasis and other dermatological diseases ( Orvis et al, 2009 ), neuromuscular diseases ( Chaudhry et al, 2001 ), organ transplants and autoimmune diseases ( Appel, Radhakrishnan & Ginzler, 2005 ). It is considered a corticosteroid-sparing agent in eye inflammation ( Thorne et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

Mycophenolate suppresses inflammation by inhibiting prostaglandin synthases: a study of molecular and experimental drug repurposing

Al-Hizab

Kandeel

2021

PeerJ

View full text Add to dashboard Cite

Mycophenolate mofetil is an established anti-proliferative and immune-suppressive agent that minimizes the proliferation of inflammatory cells by interfering with nucleic acid synthesis. Herein, we report our discovery of the prostaglandin inhibiting properties of MMF, which offers new applications for the drug in the treatment of inflammatory diseases. The estimated values of IC50MMFCOX-1, IC50MMFCOX-2, and IC50MMF5-LOX were 5.53, 0.19, and 4.47 µM, respectively. In contrast, mycophenolic acid (MPA) showed slightly stronger inhibition: IC50MPACOX-1, IC50MPACOX-2, and IC50MPA5-LOX were 4.62, 0.14, and 4.49 µM, respectively. These results indicate that MMF and MPA are, respectively, 28.6 and 33 times more selective for cyclooxygenase-2 than for cyclooxygenase-1, which implies that MMF would have less impact on the gastric mucosa than most nonselective, nonsteroidal anti-inflammatory drugs. Furthermore, MMF provided dose-dependent relief of acute inflammation in the carrageenan-induced rat paw edema test, with results comparable to those of celecoxib and indomethacin. Molecular dynamics simulations indicated that the MMF bond with COX-2 was stable, as evidenced by a low root-mean-square deviation of atomic positions, complementary per-residue root-mean-square fluctuation, and 0–4 hydrogen bonds during the 50-ns simulation time. Therefore, MMF provides immune-suppressing, cyclooxygenase-inhibiting, and inflammation-relieving properties. Our results indicate that MMF can be 1) repositioned for inflammation treatment without the need for further expensive clinical trials, 2) used for local acute inflammations, and 3) used as a sparing agent for other steroid and non-steroid anti-inflammatory medications, especially in topical applications.

show abstract

Therapeutic potential and molecular mechanisms of mycophenolic acid as an anticancer agent

Cited by 31 publications

References 56 publications

Identification of natural product modulators of Merkel cell carcinoma cell growth and survival

Identification of natural product modulators of Merkel cell carcinoma cell growth and survival

Effects of Corticosteroid Treatment on Mycophenolic Acid Exposure in Renal Transplant Patients—Results From the SAILOR Study

Mycophenolate suppresses inflammation by inhibiting prostaglandin synthases: a study of molecular and experimental drug repurposing

Contact Info

Product

Resources

About