Collateral sensitivity as a strategy against cancer multidrug resistance

Pluchino, Kristen M.; Hall, Matthew D.; Goldsborough, Andrew S.; Callaghan, Richard; Gottesman, Michael M.

doi:10.1016/j.drup.2012.03.002

Cited by 281 publications

(229 citation statements)

References 61 publications

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“…Our results confirm that multidrug-resistant cells exhibit collateral sensitivity to selected compounds. However, in contrast to the isatin-β-thiosemicarbazones (1a-e), the selective toxicity of the newly investigated compounds (2c, 3a, 4c, 4b, 5b, 5a, 6a, 6b) was not influenced by the P-gp inhibitor Tariquidar (TQ), suggesting that the observed hypersensitivity of the MDR cells cannot be exclusively linked to the activity of P-gp, and should be rather explained by off-target effects linked to other specific resistance mechanisms or the genetic drift of the selected cells [39,71,72]. In a similar manner, enhanced toxicity of the N-(2-mercaptopropionyl)glycine tiopronin against a subset of (but not all investigated)…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…Another example is the natural product Austocystin D, which possesses increased toxicity against some MDR cell lines as a result of increased activation by cytochrome P450 [75]. Increased sensitivity of MDR cells to the antimetabolite 2-deoxy-dglucose, the electron transport chain inhibitors rotenone and antimycin A [71,76,77] as well as certain P-gp-substrates [72,[78][79][80] were explained by the ATP depleting effect of the transporter. According to this model, increased glycolysis compensates for the higher energy demand created by the "futile cycling" of the transporter [79,81,82], but the oxidative stress associated with oxidative phosphorylation ultimately results in the selective apoptosis of MDR cells [83].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

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Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Pape

Tóth

Füredi

et al. 2016

European Journal of Medicinal Chemistry

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Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Pape

Tóth

Füredi

et al. 2016

European Journal of Medicinal Chemistry

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“…Even though the energy use for xenobiotic protection by efflux transporters is a small percentage of total aerobic respiration, it could become a significant drain if food is limiting and/or transporter expression is elevated. A rapid increase in mitochondrial respiration for fueling transporter activity at the onset of exposure to a substrate could be particularly deleterious because it utilizes short-term energy and simultaneously increases reactive oxygen species production by forcing mitochondria into peak levels of activity (Hall et al, 2009;Pluchino et al, 2012). This would all be exacerbated for futile substrates.…”

Section: Obligate Versus Discretionary Costs In An Energy Budgetmentioning

confidence: 99%

“…We have shown in embryos that even futile cycling is unlikely to represent a significant cost as a result of reaching a maximal transporter capacity at sufficient substrate concentrations. However, if transporter titer is elevated, such as in ABCB overexpressing drugresistant cells, exposure to typically benign chemicals that are transporter substrates can result in cell death (Pluchino et al, 2012). Referred to as collateral sensitivity, this most likely arises through secondary effects of transporter activity such as excess production of reactive oxygen species (Hall et al, 2009).…”

Section: Potential For Decreased Fitnessmentioning

confidence: 99%

Cost, effectiveness and environmental relevance of multidrug transporters in sea urchin embryos

Cole

Hamdoun

Epel

2013

Journal of Experimental Biology

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SUMMARY ATP-binding cassette transporters protect cells via efflux of xenobiotics and endogenous byproducts of detoxification. While the cost of this ATP-dependent extrusion is known at the molecular level, i.e. the ATP used for each efflux event, the overall cost to a cell or organism of operating this defense is unclear, especially as the cost of efflux changes depending on environmental conditions. During prolonged exposure to xenobiotics, multidrug transporter activity could be costly and ineffective because effluxed substrate molecules are not modified in the process and could thus undergo repeated cycles of efflux and re-entry. Here we use embryos of the purple sea urchin, Strongylocentrotus purpuratus, as a model to determine transport costs and benefits under environmentally relevant xenobiotic concentrations. Strikingly, our results show that efflux transporter activity costs less than 0.2% of total ATP usage, as a proportion of oxygen consumption. The benefits of transport, defined as the reduction in substrate accumulation due to transporter activity, depended largely, but not entirely, on the rate of passive flux of each substrate across the plasma membrane. One of the substrates tested exhibited rapid membrane permeation coupled with high rates of efflux, thus inducing rapid and futile cycles of efflux followed by re-entry of the substrate. This combination significantly reduced transporter effectiveness as a defense and increased costs even at relatively low substrate concentrations. Despite these effects with certain substrates, our results show that efflux transporters are a remarkably effective and low-cost first line of defense against exposure to environmentally relevant concentrations of xenobiotics.

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“…However, resistance to these anticancer drugs, which limits the effectiveness of chemotherapy, has been reported. 3,4) In order to overcome this issue, novel combination therapy using epigenetic modifiers is expected. Clinical trials on combination therapy have been performed using solid tumors including CRC.…”

mentioning

confidence: 99%

Different Schedule-Dependent Effects of Epigenetic Modifiers on Cytotoxicity by Anticancer Drugs in Colorectal Cancer Cells

Hosokawa

Tanaka

Iwakawa

2017

Biological & Pharmaceutical Bulletin

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Limited information is currently available on how to apply epigenetic modifiers to current colorectal cancer (CRC) chemotherapy. The purpose of this study is to clarify the schedule-dependent effects of combined treatment with conventional anticancer drugs and epigenetic modifiers in human CRC cells. Cytotoxicity in 4 CRC cell lines (SW480, HT29, SW48, and HCT116) was measured using the WST-8 assay. As epigenetic modifiers, 3 DNA methyltransferase (DNMT) inhibitors such as decitabine (DAC), azacytidine (AC), and zebularine (Zeb), and 3 histone deacetylase (HDAC) inhibitors including trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and valproic acid (VPA) were used. Combination effects were analyzed by the isobologram method. SW480 cells showed the lowest sensitivity to the anticancer drugs 5-fluorouracil, SN-38 (the active form of irinotecan), and oxaliplatin. In SW480 cells, epigenetic modifiers other than VPA showed the most significant synergistic effects when used before anticancer drugs, while VPA showed synergistic effects in co-or post-treatment. In the 3 other CRC cells, synergistic effects were less frequent and weaker. The dose of anticancer drugs may be reduced by combining epigenetic modifiers in SW480 cells, which are less sensitive to anticancer drugs, unlike the more sensitive HT29, SW48, and HCT116 cell lines. These results provide useful information for understanding how to incorporate epigenetic modifiers into current CRC chemotherapy.Key words schedule-dependent treatment; epigenetic therapy; colorectal cancer; DNA methyltransferase inhibitor; histone deacetylase inhibitor Epigenetic alterations such as DNA methylation and histone modifications have been identified as a crucial driving force in the initiation and progression of cancer.1) Since epigenetic alterations are reversible, epigenetic modifiers may be beneficial in chemotherapy.2) Several epigenetic modifiers including DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors have been approved by U.S. Food and Drug Administration (FDA) for the treatment of cancer.Combined chemotherapy, including 5-fluorouracil (5-FU) and either irinotecan (CPT-11) or oxaliplatin (L-OHP), has improved the survival period of metastatic colorectal cancer (CRC). However, resistance to these anticancer drugs, which limits the effectiveness of chemotherapy, has been reported. 3,4) In order to overcome this issue, novel combination therapy using epigenetic modifiers is expected. Clinical trials on combination therapy have been performed using solid tumors including CRC.5,6) However, there is not enough integrated information on how to apply epigenetic modifiers to current CRC chemotherapy. We previously reported that a co-treatment with decitabine (DAC, 5-aza-2′-deoxycytidine), a DNMT inhibitor, and L-OHP exerted the most potent synergistic effects among the combinations tested using 5 epigenetic modifiers and 5-FU, CPT-11, or L-OHP in 4 different CRC cell lines. 7)The treatment schedule is important for effective cancer ...

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Collateral sensitivity as a strategy against cancer multidrug resistance

Cited by 281 publications

References 61 publications

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Cost, effectiveness and environmental relevance of multidrug transporters in sea urchin embryos

Different Schedule-Dependent Effects of Epigenetic Modifiers on Cytotoxicity by Anticancer Drugs in Colorectal Cancer Cells

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