Multidrug resistance in cancer: role of ATP–dependent transporters

Gottesman, Michael M.; Fojo, Tito; Bates, Susan E.

doi:10.1038/nrc706

Cited by 4,960 publications

(4,205 citation statements)

References 133 publications

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“…The hydrophilic drugs usually can enter into cells by piggybacking on transporters that are responsible for transporting nutrients and specific agents into cells through endocytosis, but it may fail to accumulate inside MDR cancer cells instead of the efflux effect 27. For instance, Shen et al found that cisplatin‐resistant cancer cells showed pleiotropic defects, associated with reduced plasma membrane protein, which finally reduced accumulation of drugs and became cross‐resistance to anticancer drugs,28 while there was no obvious overexpression of energy‐dependent efflux transporters.…”

Section: Mechanisms Of Cancer Multidrug Resistancementioning

confidence: 99%

“…Even worse, the recurrent tumors often produce a population of MDR cancer cells, in order to make it more malignant, that spread quickly and are resistant to radiotherapy or previously treated drugs. CSCs have been reported to express a high level of drug efflux proteins, such as P‐gp, MRP1, and BCRP, to help CSCs avoid damages from cytotoxic drugs and resist to chemotherapy 2, 27, 53. Furthermore, CSCs also demonstrated active DNA‐repair and detoxification capacity, for example, the expression of Aldehyde dehydrogenases1 (ALDH1), a molecular metabolic detoxification enzyme for catalyzing oxidation of aldehyde formation in alcohol metabolism,54 has been frequently elevated as investigated in some CSC cell lines to activate tumor recurrence 55.…”

Section: Mechanisms Of Cancer Multidrug Resistancementioning

confidence: 99%

“…However, their unfavorable pharmacokinetics and side effects make it difficult to overcome drug resistance directly, even when combined with chemotherapeutics 27. The difficulty may be due to the differences of pharmacokinetics and tumor accumulation between the anticancer drugs and modulators, making it difficult to achieve synergistic effects 78.…”

Section: Inorganic Nanocarriers Overcoming Drug Resistance For Cancermentioning

confidence: 99%

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Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics

et al. 2016

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Cancer multidrug resistance (MDR) could lead to therapeutic failure of chemotherapy and radiotherapy, and has become one of the main obstacles to successful cancer treatment. Some advanced drug delivery platforms, such as inorganic nanocarriers, demonstrate a high potential for cancer theranostic to overcome the cancer‐specific limitation of conventional low‐molecular‐weight anticancer agents and imaging probes. Specifically, it could achieve synergetic therapeutic effects, demonstrating stronger killing effects to MDR cancer cells by combining the inorganic nanocarriers with other treatment manners, such as RNA interference and thermal therapy. Moreover, the inorganic nanocarriers could provide imaging functions to help monitor treatment responses, e.g., drug resistance and therapeutic effects, as well as analyze the mechanism of MDR by molecular imaging modalities. In this review, the mechanisms involved in cancer MDR and recent advances of applying inorganic nanocarriers for MDR cancer imaging and therapy are summarized. The inorganic nanocarriers may circumvent cancer MDR for effective therapy and provide a way to track the therapeutic processes for real‐time molecular imaging, demonstrating high performance in studying the interaction of nanocarriers and MDR cancer cells/tissues in laboratory study and further shedding light on elaborate design of nanocarriers that could overcome MDR for clinical translation.

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Section: Mechanisms Of Cancer Multidrug Resistancementioning

confidence: 99%

Section: Mechanisms Of Cancer Multidrug Resistancementioning

confidence: 99%

Section: Inorganic Nanocarriers Overcoming Drug Resistance For Cancermentioning

confidence: 99%

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Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics

et al. 2016

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“…An emerging strategy for enhanced CNS delivery is co-administration of such compounds with inhibitors of drug efflux transporters [289][290][291]. First generation Pgp inhibitors include Pgp substrates, such as cyclosporine A and verapamil.…”

Section: Polymeric Inhibitors Of Drug Efflux Systems In Bbbmentioning

confidence: 99%

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

Kabanov

Gendelman

2007

Progress in Polymer Science

242

139

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Neurodegenerative and infectious disorders including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke are rapidly increasing as population's age. Alzheimer's disease alone currently affects 4.5 million Americans, and more than $100 billion is spent per year on medical and institutional care for affected people. Such numbers will double in the ensuing decades. Currently disease diagnosis for all disorders is made, in large measure, on clinical grounds as laboratory and neuroimaging tests confirm what is seen by more routine examination. Achieving early diagnosis would enable improved disease outcomes. Drugs, vaccines or regenerative proteins present "real" possibilities for positively affecting disease outcomes, but are limited in that their entry into the brain is commonly restricted across the blood-brain barrier. This review highlights how these obstacles can be overcome by polymer science and nanotechnology. Such approaches may improve diagnostic and therapeutic outcomes. New developments in polymer science coupled with cell-based delivery strategies support the notion that diseases that now have limited therapeutic options can show improved outcomes by advances in nanomedicine.

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“…ABC transporter proteins confer drug resistance by actively transporting drugs from the intracellular space to the extracellular space, thereby preventing the interaction of these drugs with their intracellular targets. In the case of ABCB1, expression has been shown to confer resistance to vinca alkaloids, anthracyclines, taxanes, epipodophyllotoxins, and other drugs 9, 10 .…”

Section: Introductionmentioning

confidence: 99%

A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

et al. 2017

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We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1 + cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

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Multidrug resistance in cancer: role of ATP–dependent transporters

Cited by 4,960 publications

References 133 publications

Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics

Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

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