Multidrug Resistance Reversal Agents

Robert, Jacques; Jarry, Christian

doi:10.1021/jm030183a

Cited by 277 publications

(184 citation statements)

References 125 publications

(253 reference statements)

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“…Usually such compounds are considered as P-gp inhibitors. 28,29 Through calculating, a basic approximation can be obtained, but the differences are low and multifactorial. The most active one, Euphorbia factor L 2 (3) with substitution of benzoyl group at C-7 has the highest molecular weight value (MW = 643), molecular volume (MV = 593), log P value (7.9) and the highest number of hydrogen bond acceptor groups (9H-bond acceptors).…”

Section: Biological Evaluation and Structure-activity Relationshipsmentioning

confidence: 99%

Lathyrane diterpenes from Euphorbia lathyris as modulators of multidrug resistance and their crystal structures

Jiao

Dong

et al. 2009

Bioorganic & Medicinal Chemistry

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Section: Biological Evaluation and Structure-activity Relationshipsmentioning

confidence: 99%

Lathyrane diterpenes from Euphorbia lathyris as modulators of multidrug resistance and their crystal structures

Jiao

Dong

et al. 2009

Bioorganic & Medicinal Chemistry

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“…27) However, few of these MDR reverters achieve clinical success. Actually, there are currently no reversal agents clinically available.…”

Section: Discussionmentioning

confidence: 99%

“…A major reason for this lack of clinical success is owing to the deleterious effect of the reversal agents on normal tissues expressing P-gp and their intrinsic toxicities in vivo. 27) This has been the major problem encountering for the second and third generations of MDR reversal agents. Therefore, development of potent yet selective P-gp inhibitors remains to be a major task for this field of research.…”

Section: Discussionmentioning

confidence: 99%

Reversal of P-Glycoprotein Mediated Multidrug Resistance in K562 Cell Line by a Novel Synthetic Calmodulin Inhibitor, E6

Zhu

Wang

Guo

et al. 2005

Biological & Pharmaceutical Bulletin

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Multidrug resistance (MDR) has been thought to be one of the major obstacles for successful chemotherapy in patients with cancers. The MDR has been associated with overexpression of P-glycoprotein (P-gp) in cancer cells.1) P-gp is a 170-to 180-kDa plasma membrane glycoprotein. P-gp belongs to the superfamily of ATP-binding cassette (ABC) transporters and actively effluxes a wide range of structurally diverse amphipathic anticancer agents. The efflux function of P-gp can decrease drug concentrations in tumor cells and result in chemotherapeutic failure. P-gp mediated MDR has also been associated with inhibition of multiple forms of caspase-dependent tumor cell apoptosis. 2-4)It has been demonstrated that some P-gp inhibitors could effectively reverse P-gp mediated MDR in in vitro experiments. Among the P-gp inhibitors identified, verapamil (VER) was the first which has potent effect on reversal of MDR through inhibition of P-gp.5) Subsequently, a number of other structurally unrelated compounds such as cyclosporin, phenothiazines, antimalarials and antibiotics have also been demonstrated to be effective P-gp inhibitors of Pgp.6,7) However many of these compounds are fail to be introduced to clinical trails due to the unacceptable toxicities for anticancer treatment or nonspecific and weak inhibitory effect on P-gp. Therefore, the development of newer P-gp inhibitors with higher selectivity and stronger potency remains a major goal for this field of research.Calmodulin is a calcium-binding protein that may play a role in the signaling of insulin-and contraction-stimulated glucose transport. 8) Calmodulin inhibitors may therefore inhibit both contraction/hypoxia-and insulin-stimulated glucose transport. Several calmodulin inhibitors have been found to reverse MDR by inhibiting the P-gp mediated drug efflux.9-17) E6, a derivative of berbamine which belongs to bi-bezylisoquinolines, was synthesized by China Pharmaceutical University and exhibited potent calmodulin antagonistic activity (Fig. 1).18) Our previous study showed that E6 exhibited strong inhibitory effect on the activity of P-gp in rat brain microvessel endothelial cells (RBMECs). 19) However, the possible reversal effect of E6 on MDR cancer cells has not been investigated. In the present study, we studied the effect of E6 on MDR of K562/DOX cell line that has overexpression of P-gp. 20) In addition, these effects were compared with those in K562 parent cell line. Furthermore, the effect of E6 on the doxorubicin-induced apoptosis were studied and compared in both K562/DOX and K562 parent cells. MATERIALS AND METHODSChemicals E6 was kindly provided by Dr. Wen-Long Hwang (China Pharmaceutical University). 3-(4,5-Dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT), doxorubicin and VER were purchased from Sigma-Aldrich (St. Louis, MO, U.S.A.). FITC-annexin V and propidium iodide The overexpression of P-glycoprotein (P-gp) is associated with multidrug resistance (MDR) of tumor cells to a number of chemotherapeutic drugs. P-gp inhibitors have been shown to ef...

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“…To overcome ABC transporter-mediated resistance, various approaches have been exploited, including the development of drugs that specifically inhibit ABC family members. However, up to now, most of the phase III clinical trials with such inhibitors have failed (Robert & Jarry 2003, Shukla et al 2011, Bugde et al 2017. Interestingly, it has been recently reported that the antiandrogens bicalutamide and enzalutamide inhibit ABCB1 efflux activity.…”

Section: Mechanisms Of Acquired Resistance To Amcdsmentioning

confidence: 99%

Fighting tubulin-targeting anticancer drug toxicity and resistance

Visconti

Grieco

2017

Endocrine-Related Cancer

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Tubulin-targeting drugs, like taxanes and vinca alkaloids, are among the most effective anticancer therapeutics used in the clinic today. Specifically, anti-microtubule cancer drugs (AMCDs) have proven to be effective in the treatment of castration-resistant prostate cancer and triple-negative breast cancer. AMCDs, however, have limiting toxicities that include neutropenia and neurotoxicity, and, in addition, tumor cells can become resistant to the drugs after long-term use. Co-targeting mitotic progression/ slippage with inhibition of the protein kinases WEE1 and MYT1 that regulate CDK1 kinase activity may improve AMCD efficacy, reducing the acquisition of resistance by the tumor and side effects from the drug and/or its vehicle. Other possible treatments that improve outcomes in the clinic for these two drug-resistant cancers, including new formulations of the AMCDs and pursuing different molecular targets, will be discussed.

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Multidrug Resistance Reversal Agents

Cited by 277 publications

References 125 publications

Lathyrane diterpenes from Euphorbia lathyris as modulators of multidrug resistance and their crystal structures

Lathyrane diterpenes from Euphorbia lathyris as modulators of multidrug resistance and their crystal structures

Reversal of P-Glycoprotein Mediated Multidrug Resistance in K562 Cell Line by a Novel Synthetic Calmodulin Inhibitor, E6

Fighting tubulin-targeting anticancer drug toxicity and resistance

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