Targeting multidrug resistance in cancer

Szakács, Gergely; Paterson, Jill K.; Ludwig, Joseph A.; Booth-Genthe, Catherine; Gottesman, Michael M.

doi:10.1038/nrd1984

Cited by 3,195 publications

(2,894 citation statements)

References 210 publications

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“…Membrane transporters of the ABC superfamily function as a pump, and can lead to resistance against multiple anticancer agents (Gottesman et al, 2002; Clock and ATF4 expression and drug resistance T Igarashi et al Szakacs et al, 2006). Among these transporters, P-glycoprotein and the MRP families have been extensively studied (Annereau et al, 2004).…”

Section: Clock and Atf4 Expression And Drug Resistancementioning

confidence: 99%

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

et al. 2007

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The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatinresistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression of many genes that regulate hormone release, cell division, sleep-awake cycle and tumor growth. We demonstrate that ATF4 is a direct target of Clock, and that Clock is overexpressed in cisplatin-resistant cells. Furthermore, Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. Notably, ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy.

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Section: Clock and Atf4 Expression And Drug Resistancementioning

confidence: 99%

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

et al. 2007

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“…The most encountered drug resistance is caused by increased drug efflux from cancer cells, which is mediated by the ATP binding cassette (ABC) family of membrane transporters 12. Until now, over 48 types of ABC transporters have been identified in humans, and over 12 of them have been reported to cause drug resistance.…”

Section: Mechanisms Of Cancer Multidrug Resistancementioning

confidence: 99%

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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“…This subfamily includes ABCC1 (MRP1, discovered in 1992), ABCC2 (MRP2), ABCC3 (MRP3), ABCC4 (MRP4), ABCC5 (MRP5), ABCC10 (MRP7), ABC11 (MRP8), and ABC12 (MRP9) ( Table 1). ABCB1 (MDR1) and ABCG2 (BCRP) are also known for imparting a multidrug resistant phenotype [17]. The substrates that these transporters recognize are very diverse in structure.…”

Section: Abc Transporters and Drug Resistancementioning

confidence: 99%

Harnessing drug resistance: Using ABC transporter proteins to target cancer cells

Leitner

Kachadourian

Day

2007

Biochemical Pharmacology

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The ATP-binding cassette (ABC) class of proteins is one of the most functionally diverse transporter families found in biological systems. Although the abundance of ABC proteins varies between species, they are highly conserved in sequence and often demonstrate similar functions across prokaryotic and eukaryotic organisms. Beginning with a brief summary of the events leading to our present day knowledge of ABC transporters, the purpose of this review is to discuss the potential for utilizing ABC transporters as a means for cellular glutathione (GSH) modulation. GSH is one of the most abundant thiol antioxidants in cells. It is involved in cellular division, protein and DNA synthesis, maintenance of cellular redox status and xenobiotic metabolism. Cellular GSH levels are often altered in many disease states including cancer. Over the past two decades there has been considerable emphasis on methods to sensitize cancer cells to chemotherapeutics and ionization radiation therapy by GSH depletion. We contend that ABC transporters, particularly multi-drug resistant proteins (MRPs), may be used as therapeutic targets for applications aimed at modulation of GSH levels. This review will emphasize MRP-mediated modulation of intracellular GSH levels as a potential alternative and adjunctive approach for cancer therapy.

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Targeting multidrug resistance in cancer

Cited by 3,195 publications

References 210 publications

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

Inorganic Nanocarriers Overcoming Multidrug Resistance for Cancer Theranostics

Harnessing drug resistance: Using ABC transporter proteins to target cancer cells

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