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Defined lipid analogues induce transient channels to facilitate drug-membrane traversal and circumvent cancer therapy resistance.

van Hell AJ, Melo MN, van Blitterswijk WJ, Gueth DM, Braumuller TM, Pedrosa LR, Song JY, Marrink SJ, Koning GA, Jonkers J, Verheij M - Sci Rep (2013)

Bottom Line: Well-defined lipid analogues adapt to the amphiphilic drug doxorubicin, when co-inserted into the cell membrane, and assemble a transient channel that rapidly facilitates the translocation of the drug onto the intracellular membrane leaflet.Molecular dynamic simulations unveiled the structure and dynamics of membrane channel assembly.Our results illuminate the role of the plasma membrane in restricting the efficacy of established therapies and drug resistance - and provide a mechanism to overcome ineffectiveness of existing and candidate drugs.

View Article: PubMed Central - PubMed

Affiliation: The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Divisions of Biological Stress Responses, Amsterdam, The Netherlands.

ABSTRACT
Design and efficacy of bioactive drugs is restricted by their (in)ability to traverse cellular membranes. Therapy resistance, a major cause of ineffective cancer treatment, is frequently due to suboptimal intracellular accumulation of the drug. We report a molecular mechanism that promotes trans-membrane movement of a stereotypical, widely used anti-cancer agent to counteract resistance. Well-defined lipid analogues adapt to the amphiphilic drug doxorubicin, when co-inserted into the cell membrane, and assemble a transient channel that rapidly facilitates the translocation of the drug onto the intracellular membrane leaflet. Molecular dynamic simulations unveiled the structure and dynamics of membrane channel assembly. We demonstrate that this principle successfully addresses multi-drug resistance of genetically engineered mouse breast cancer models. Our results illuminate the role of the plasma membrane in restricting the efficacy of established therapies and drug resistance - and provide a mechanism to overcome ineffectiveness of existing and candidate drugs.

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Co-administration of GC provides superior anti-tumour efficacy in multi-drug resistant mammary tumours.(A) GC re-sensitize tumours to doxorubicin therapy in a heterogeneous tumour population; in the LDox GC cohort, average tumour size (±SEM, n = 9) was significantly reduced at day 21, compared to LDox (without GC) (p < 0.05). Arrows indicate time points of drug dosing. (B) LDox GC is the only treatment that significantly prolongs median survival by 2.7-fold over untreated control (p < 0.001). (C) H&E stained specimen of bone marrow (C, upper) and spleen (C, lower). Doxorubicin treatment severely depletes erythropoietic cells (dark-blue stained) (C, right), compared to control tissue (C, left) (bars 20 μm). (D) Incidence (%) of reduced erythropoiesis in numbers of organs per treatment group. Compared to control (6/30), depletion of erythropoiesis was seen in fDox (12/24) and LDox (18/32) groups, but less for GC co-administration (12/30).
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f5: Co-administration of GC provides superior anti-tumour efficacy in multi-drug resistant mammary tumours.(A) GC re-sensitize tumours to doxorubicin therapy in a heterogeneous tumour population; in the LDox GC cohort, average tumour size (±SEM, n = 9) was significantly reduced at day 21, compared to LDox (without GC) (p < 0.05). Arrows indicate time points of drug dosing. (B) LDox GC is the only treatment that significantly prolongs median survival by 2.7-fold over untreated control (p < 0.001). (C) H&E stained specimen of bone marrow (C, upper) and spleen (C, lower). Doxorubicin treatment severely depletes erythropoietic cells (dark-blue stained) (C, right), compared to control tissue (C, left) (bars 20 μm). (D) Incidence (%) of reduced erythropoiesis in numbers of organs per treatment group. Compared to control (6/30), depletion of erythropoiesis was seen in fDox (12/24) and LDox (18/32) groups, but less for GC co-administration (12/30).

Mentions: After establishing efficacy in the WEP cultures in vitro, we assessed therapy response in the GEM model, using the clinical trial set-up, as described above. The clinically used doxorubicin formulations free doxorubicin (fDox) and conventional liposomal doxorubicin (LDox) were administered at MTD, LDox GC was applied at equidose to LDox (10 mg/kg), while untreated tumours served as control. As depicted in Fig. 5A, LDox (without GC) generated an initial anti-tumour effect, more so than free doxorubicin (fDox), but tumours finally progressed despite additional dosing in either group. However, when GC is present (LDox GC; 10 mg/kg) a sustained inhibition of tumour progression was observed. At day 21 of treatment in the LDox GC group, tumour size was significantly reduced over LDox (p < 0.05), by two-fold (Fig. 5A).


Defined lipid analogues induce transient channels to facilitate drug-membrane traversal and circumvent cancer therapy resistance.

van Hell AJ, Melo MN, van Blitterswijk WJ, Gueth DM, Braumuller TM, Pedrosa LR, Song JY, Marrink SJ, Koning GA, Jonkers J, Verheij M - Sci Rep (2013)

Co-administration of GC provides superior anti-tumour efficacy in multi-drug resistant mammary tumours.(A) GC re-sensitize tumours to doxorubicin therapy in a heterogeneous tumour population; in the LDox GC cohort, average tumour size (±SEM, n = 9) was significantly reduced at day 21, compared to LDox (without GC) (p < 0.05). Arrows indicate time points of drug dosing. (B) LDox GC is the only treatment that significantly prolongs median survival by 2.7-fold over untreated control (p < 0.001). (C) H&E stained specimen of bone marrow (C, upper) and spleen (C, lower). Doxorubicin treatment severely depletes erythropoietic cells (dark-blue stained) (C, right), compared to control tissue (C, left) (bars 20 μm). (D) Incidence (%) of reduced erythropoiesis in numbers of organs per treatment group. Compared to control (6/30), depletion of erythropoiesis was seen in fDox (12/24) and LDox (18/32) groups, but less for GC co-administration (12/30).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3674426&req=5

f5: Co-administration of GC provides superior anti-tumour efficacy in multi-drug resistant mammary tumours.(A) GC re-sensitize tumours to doxorubicin therapy in a heterogeneous tumour population; in the LDox GC cohort, average tumour size (±SEM, n = 9) was significantly reduced at day 21, compared to LDox (without GC) (p < 0.05). Arrows indicate time points of drug dosing. (B) LDox GC is the only treatment that significantly prolongs median survival by 2.7-fold over untreated control (p < 0.001). (C) H&E stained specimen of bone marrow (C, upper) and spleen (C, lower). Doxorubicin treatment severely depletes erythropoietic cells (dark-blue stained) (C, right), compared to control tissue (C, left) (bars 20 μm). (D) Incidence (%) of reduced erythropoiesis in numbers of organs per treatment group. Compared to control (6/30), depletion of erythropoiesis was seen in fDox (12/24) and LDox (18/32) groups, but less for GC co-administration (12/30).
Mentions: After establishing efficacy in the WEP cultures in vitro, we assessed therapy response in the GEM model, using the clinical trial set-up, as described above. The clinically used doxorubicin formulations free doxorubicin (fDox) and conventional liposomal doxorubicin (LDox) were administered at MTD, LDox GC was applied at equidose to LDox (10 mg/kg), while untreated tumours served as control. As depicted in Fig. 5A, LDox (without GC) generated an initial anti-tumour effect, more so than free doxorubicin (fDox), but tumours finally progressed despite additional dosing in either group. However, when GC is present (LDox GC; 10 mg/kg) a sustained inhibition of tumour progression was observed. At day 21 of treatment in the LDox GC group, tumour size was significantly reduced over LDox (p < 0.05), by two-fold (Fig. 5A).

Bottom Line: Well-defined lipid analogues adapt to the amphiphilic drug doxorubicin, when co-inserted into the cell membrane, and assemble a transient channel that rapidly facilitates the translocation of the drug onto the intracellular membrane leaflet.Molecular dynamic simulations unveiled the structure and dynamics of membrane channel assembly.Our results illuminate the role of the plasma membrane in restricting the efficacy of established therapies and drug resistance - and provide a mechanism to overcome ineffectiveness of existing and candidate drugs.

View Article: PubMed Central - PubMed

Affiliation: The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Divisions of Biological Stress Responses, Amsterdam, The Netherlands.

ABSTRACT
Design and efficacy of bioactive drugs is restricted by their (in)ability to traverse cellular membranes. Therapy resistance, a major cause of ineffective cancer treatment, is frequently due to suboptimal intracellular accumulation of the drug. We report a molecular mechanism that promotes trans-membrane movement of a stereotypical, widely used anti-cancer agent to counteract resistance. Well-defined lipid analogues adapt to the amphiphilic drug doxorubicin, when co-inserted into the cell membrane, and assemble a transient channel that rapidly facilitates the translocation of the drug onto the intracellular membrane leaflet. Molecular dynamic simulations unveiled the structure and dynamics of membrane channel assembly. We demonstrate that this principle successfully addresses multi-drug resistance of genetically engineered mouse breast cancer models. Our results illuminate the role of the plasma membrane in restricting the efficacy of established therapies and drug resistance - and provide a mechanism to overcome ineffectiveness of existing and candidate drugs.

Show MeSH
Related in: MedlinePlus