A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

AbstractThe activity and potency of a drug is inherently affected by the metabolic state of its target cell. Solute Carriers (SLCs) represent the largest family of transmembrane transporters in humans and constitute major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of individual chemical compounds into cellular systems, but systematic surveys of transporter-drug relationships in human cells are currently lacking. We performed a series of genetic screens in the haploid human cell line HAP1 using a set of 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using a SLC-focused CRISPR/Cas9 lentiviral library, we identified transporters whose absence induced resistance to the drugs tested. Among the hundreds of drug-SLC relationships identified, we confirmed the role of the folate transporter SLC19A1 on the activity of antifolates and of SLC29A1 on several nucleoside analogs. Among the newly discovered dependencies, we identified the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the compounds screened suggested a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provided an experimentally validated set of SLC-drug associations for a number of clinically relevant compounds.

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NOXA as Target for the Combination Therapy of Betulinic Acid and Conventional Cytotoxic Drugs

Klinische Pädiatrie ◽

10.1055/s-0030-1270324 ◽

2010 ◽

Vol 223 (01) ◽

Author(s):

I Jeremias ◽

H Ehrhardt ◽

I Höfig ◽

N Terziyska ◽

P Obexer

Keyword(s):

Combination Therapy ◽

Betulinic Acid ◽

Cytotoxic Drugs

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Two drug combinations vs combinations of 3 or more cytotoxic drugs for metastatic breast cancer

10.1002/14651858.cd003369.pub2 ◽

2009 ◽

Author(s):

Davina Ghersi ◽

John Simes ◽

I Craig Henderson ◽

Russell Basser ◽

Christine Brunswick ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Metastatic Breast ◽

Drug Combinations ◽

Cytotoxic Drugs

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The Blockade of Tumoral IL1β-Mediated Signaling in Normal Colonic Fibroblasts Sensitizes Tumor Cells to Chemotherapy and Prevents Inflammatory CAF Activation

International Journal of Molecular Sciences ◽

10.3390/ijms22094960 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4960

Author(s):

Natalia Guillén Díaz-Maroto ◽

Gemma Garcia-Vicién ◽

Giovanna Polcaro ◽

María Bañuls ◽

Nerea Albert ◽

...

Keyword(s):

Cancer Cells ◽

Tumor Cells ◽

Cell Types ◽

Colorectal Tumor ◽

Cytotoxic Drugs ◽

Differential Sensitivity ◽

Paracrine Signaling ◽

Inflammatory Phenotype ◽

Heterotypic Interactions ◽

Carcinoma Associated Fibroblasts

Heterotypic interactions between newly transformed cells and normal surrounding cells define tumor’s fate in incipient carcinomas. Once homeostasis has been lost, normal resident fibroblasts become carcinoma-associated fibroblasts, conferring protumorogenic properties on these normal cells. Here we describe the IL1β-mediated interplay between cancer cells and normal colonic myofibroblasts (NCFs), which bestows differential sensitivity to cytotoxic drugs on tumor cells. We used NCFs, their conditioned media (CM), and cocultures with tumor cells to characterize the IL1β-mediated crosstalk between both cell types. We silenced IL1β in tumor cells to demonstrate that such cells do not exert an influence on NCFs inflammatory phenotype. Our results shows that IL1β is overexpressed in cocultured tumor cells. IL1β enables paracrine signaling in myofibroblasts, converting them into inflammatory-CAFs (iCAF). IL1β-stimulated-NCF-CM induces migration and differential sensitivity to oxaliplatin in colorectal tumor cells. Such chemoprotective effect has not been evidenced for TGFβ1-driven NCFs. IL1β induces the loss of a myofibroblastic phenotype in NCFs and acquisition of iCAF traits. In conclusion, IL1β-secreted by cancer cells modify surrounding normal fibroblasts to confer protumorogenic features on them, particularly tolerance to cytotoxic drugs. The use of IL1β-blocking agents might help to avoid the iCAF traits acquisition and consequently to counteract the protumorogenic actions these cells.

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Physical Resilience as a Determinant of Healthspan and Lifespan in Mice

Innovation in Aging ◽

10.1093/geroni/igaa057.3031 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 829-829

Author(s):

Nathan LeBrasseur

Keyword(s):

Middle Ages ◽

Interest Group ◽

Later Life ◽

Cytotoxic Drugs ◽

Geriatric Syndromes ◽

Age Related ◽

Fundamental Biology ◽

Dynamic Measures ◽

Biology Of Aging ◽

Insight Into

Abstract Dynamic measures of physical resilience—the ability to resist and recover from a challenge—may be informative of biological age far prior to overt manifestations such as age-related diseases and geriatric syndromes (i.e., frailty). If true, physical resilience at younger or middle ages may be predictive of future healthspan and lifespan, and provide a unique paradigm in which interventions targeting the fundamental biology of aging can be tested. This seminar will discuss research on the development of clinically-relevant measures of physical resilience in mice, including anesthesia, surgery, and cytotoxic drugs. It will further highlight how these measures compare between young, middle-aged, and older mice, and how mid-life resilience relates to later-life healthspan. Finally, it will provide insight into whether interventions targeting the biology of aging can modify physical resilience in mice. Part of a symposium sponsored by Epidemiology of Aging Interest Group.

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