Reviewing the mechanisms of natural product-drug interactions involving efflux transporters and metabolic enzymes

Feltrin, Clarissa; Simões, Cláudia Maria Oliveira

doi:10.1016/j.cbi.2019.108825

Cited by 20 publications

(11 citation statements)

References 235 publications

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“…The findings obtained with the extracts must be interpreted carefully if they are to be used for the benefit of patients. There are other factors such as pharmacokinetics and bioavailability [ 56 ], synergy or antagonism [ 57 , 58 ], and the adverse effects that the consumption of natural products can have that have not been developed correctly [ 59 ] and that can affect the patient, reducing their quality of life and the effect of allopathic therapy of choice.…”

Section: Discussionmentioning

confidence: 99%

Preferential Activity of Petiveria alliacea Extract on Primary Myeloid Leukemic Blast

Ballesteros-Ramírez

Aldana

Herrera

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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The need for new therapeutic approaches to improve the response in acute leukemia (AL), either by directing therapy or with new therapeutic alternatives, has been a research and clinical interest topic. We evaluated whether blasts from AL patients were sensitive ex vivo to the induction chemotherapy and whether the extracts of Petiveria alliacea (Anamu SC) and Caesalpinia spinosa (P2Et) modulated the sensitivity of leukemic cells to death. Bone marrow samples were taken from 26 patients with de novo AL and 6 in relapse, and the cytotoxicity of the extracts alone or in combination with the chemotherapeutic was evaluated by XTT. Patients were classified as good (GR) and bad responders (BR) according to the ex vivo test. 70.5% of the GR patients to the ex vivo test achieved postinduction remission to induction chemotherapy with a median overall survival of 12.50 months versus 7.23 months in the two groups. Furthermore, it was found that the ex vivo response to extracts and chemotherapeutics is heterogeneous and shows an exclusive pattern between the extracts, Anamu being the more effective in inducing cell death. The combination of extracts with chemotherapeutic agents showed synergistic or antagonistic effects in the patients’ blasts. These results show that the ex vivo evaluation of the sensitivity to induction drugs using primary blasts from patients exhibits a correlation with the response to induction chemotherapy in patients. These analyses would allow establishing a system to predict response to treatment and determine ex vivo susceptibility to new therapies under development, among which is phytotherapeutics.

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Section: Discussionmentioning

confidence: 99%

Preferential Activity of Petiveria alliacea Extract on Primary Myeloid Leukemic Blast

Ballesteros-Ramírez

Aldana

Herrera

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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show abstract

“…Due to excessive drug usage, healthy or malignant cells may change their sensitivity towards exogenous substances by an increased expression or higher activity of transport pumps from ATP-binding cassette (ABC) superfamily, especially P-glycoprotein (P-gp). This situation can be overcome by competitive, non-competitive or allosteric P-gp inhibition or via affecting P-gp expression [20]. Silybin seems to be a prospective compound in this regard, as pre-incubation of P-gp-positive small-cell lung cancer (VPA17) cells at 30 µM for 5 days led to decreased IC 50 (concentration halving the viability) of etoposide [21].…”

Section: Introductionmentioning

confidence: 99%

Multidrug Resistance Modulation Activity of Silybin Derivatives and Their Anti-Inflammatory Potential

et al. 2020

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Silybin is considered to be the main biologically active component of silymarin. Its oxidized derivative 2,3-dehydrosilybin typically occurs in silymarin in small, but non-negligible amounts (up to 3%). Here, we investigated in detail complex biological activities of silybin and 2,3-dehydrosilybin optical isomers. Antioxidant activities of pure stereomers A and B of silybin and 2,3-dehydrosilybin, as well as their racemic mixtures, were investigated by using oxygen radical absorption capacity (ORAC) and cellular antioxidant activity (CAA) assay. All substances efficiently reduced nitric oxide production and cytokines (TNF-α, IL-6) release in a dose-dependent manner. Multidrug resistance (MDR) modulating potential was evaluated as inhibition of P-glycoprotein (P-gp) ATPase activity and regulation of ATP-binding cassette (ABC) protein expression. All the tested compounds showed strong dose-dependent inhibition of P-gp pump. Moreover, 2,3-dehydrosilybin A (30 µM) displayed the strongest sensitization of doxorubicin-resistant ovarian carcinoma. Despite these significant effects, silybin B was the only compound acting directly upon P-gp in vitro and also downregulating the expression of respective MDR genes. This compound altered the expression of P-glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). 2,3-Dehydrosilybin AB exhibited the most effective inhibition of acetylcholinesterase activity. We can clearly postulate that silybin derivatives could serve well as modulators of a cancer drug-resistant phenotype.

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“…Recently, we have demonstrated that paeonol can also protect against testicular ischemia-reperfusion injury [ 19 ]. On the other hand, the expression and/or activity of P-gp can be modulated by numerous natural products [ 20 ]; meanwhile, P-gp accepts paeonol as a substrate [ 21 ]. To the best of our knowledge, previous studies neither evaluated the protective effect of paeonol against MTX-induced testicular injury nor described the role of P-gp in paeonol protection against any testicular injury model.…”

Section: Introductionmentioning

confidence: 99%

The Possible Contribution of P-Glycoprotein in the Protective Effect of Paeonol against Methotrexate-Induced Testicular Injury in Rats

et al. 2020

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Paeonol, a phenolic ingredient in the genus Paeonia, possesses antioxidant and anti-inflammatory effects. Methotrexate (MTX) is a commonly used chemotherapeutic agent; however, its germ cell damage is a critical problem. P-glycoprotein (P-gp), an efflux transporter, is a member of the blood–testis barrier. The present study evaluated the protective effect of paeonol on MTX-induced testicular injury in rats with the exploration of its mechanism and the possible contribution of P-gp in such protection. Testicular weight, serum testosterone, and testicular P-gp levels were measured. Testicular oxidant/antioxidant status was evaluated via determining the levels of malondialdehyde, total nitrite, reduced glutathione, and superoxide dismutase activity. The inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and the apoptotic marker caspase 3 were estimated immunohistochemically. Testicular histopathology and spermatogenesis scores were also examined. MTX caused histopathologically evident testicular damage with decreased testicular weight, testosterone level, and spermatogenesis score, as well as significant increases in oxidative, inflammatory, and apoptotic responses. Paeonol significantly restored testicular weight, testosterone level, spermatogenesis score, and oxidant/antioxidant balance. Moreover, paeonol increased the testicular P-gp level and significantly decreased TNF-α and caspase 3 immunostaining. In conclusion, paeonol offered a protective effect against MTX-induced testicular injury through its antioxidant, anti-inflammatory, and antiapoptotic effects, as well as by increasing testicular P-gp level.

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Reviewing the mechanisms of natural product-drug interactions involving efflux transporters and metabolic enzymes

Cited by 20 publications

References 235 publications

Preferential Activity of Petiveria alliacea Extract on Primary Myeloid Leukemic Blast

Preferential Activity of Petiveria alliacea Extract on Primary Myeloid Leukemic Blast

Multidrug Resistance Modulation Activity of Silybin Derivatives and Their Anti-Inflammatory Potential

The Possible Contribution of P-Glycoprotein in the Protective Effect of Paeonol against Methotrexate-Induced Testicular Injury in Rats

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