Glabratephrin reverses doxorubicin resistance in triple negative breast cancer by inhibiting P-glycoprotein

Triple negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and a worse clinical outcome compared with other breast cancer subtypes. Doxorubicin is considered to be one of the most effective agents in the treatment of TNBC. Unfortunately, resistance to this agent is common. In some drug-resistant cells, drug efflux is mediated by adenosine triphosphate-dependent membrane transporter termed adenosine triphosphate-binding cassette (ABC) transporter, which can drive the substrates across membranes against concentration gradient. In the tumor microenvironment, upon interaction with mesenchymal stem cells (MSCs), tumor cells exhibit altered biological functions of certain gene clusters, hence increasing stemness of tumor cells, migration ability, angiogenesis, and drug resistance. In our present study, we investigated the mechanism of TNBC drug resistance induced by adipose-derived MSCs. Upon exposure of TNBC to MSC-secreted conditioned medium (CM), noticeable drug resistance against doxorubicin with markedly increased BCRP protein expression was observed. Intracellular doxorubicin accumulation of TNBC was also decreased by MSC-secreted CM. Furthermore, we found that doxorubicin resistance of TNBC was mediated by IL-8 presented in the MSC-secreted CM. These findings may enrich the list of potential targets for overcoming drug resistance induced by MSCs in TNBC patients.

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Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer

10.1101/2020.08.04.235697 ◽

2020 ◽

Author(s):

Samantha A Hutchinson ◽

Alex Websdale ◽

Giorgia Cioccoloni ◽

Hanne Røberg-Larsen ◽

Priscilia Lianto ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Chemotherapy Resistance ◽

Resistance Mechanism ◽

P Glycoprotein ◽

Tumor Tissues ◽

X Receptors ◽

Necessary And Sufficient

AbstractTriple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases.

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Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells

Pharmaceutics ◽

10.3390/pharmaceutics12020096 ◽

2020 ◽

Vol 12 (2) ◽

pp. 96 ◽

Cited By ~ 12

Author(s):

Gamal-Eldein Fathy Abd-Ellatef ◽

Elena Gazzano ◽

Daniela Chirio ◽

Ahmed Ragab Hamed ◽

Dimas Carolina Belisario ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Transcriptional Activation ◽

Solid Lipid Nanoparticles ◽

Plasma Membranes ◽

Triple Negative ◽

Lipid Nanoparticles ◽

Solid Lipid ◽

P Glycoprotein ◽

Main Thing

Multidrug resistance (MDR) is a critical hindrance to the success of cancer chemotherapy. The main thing responsible for MDR phenotypes are plasma-membranes associated with adenosine triphosphate (ATP) Binding Cassette (ABC) drug efflux transporters, such as the P-glycoprotein (Pgp) transporter that has the broadest spectrum of substrates. Curcumin (CURC) is a Pgp inhibitor, but it is poorly soluble and bioavailable. To overcome these limitations, we validated the efficacy and safety of CURC, loaded in biocompatible solid lipid nanoparticles (SLNs), with or without chitosan coating, with the goal of increasing the stability, homogeneous water dispersibility, and cellular uptake. Both CURC-loaded SLNs were 5–10-fold more effective than free CURC in increasing the intracellular retention and toxicity of doxorubicin in Pgp-expressing triple negative breast cancer (TNBC). The effect was due to the decrease of intracellular reactive oxygen species, consequent inhibition of the Akt/IKKα-β/NF-kB axis, and reduced transcriptional activation of the Pgp promoter by p65/p50 NF-kB. CURC-loaded SLNs also effectively rescued the sensitivity to doxorubicin against drug-resistant TNBC tumors, without signs of systemic toxicity. These results suggest that the combination therapy, based on CURC-loaded SLNs and doxorubicin, is an effective and safe approach to overcome the Pgp-mediated chemoresistance in TNBC.

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Chromosome Instability Associates with Radiation and Doxorubicin Resistance in Triple Negative Breast Cancer Cell Lines.

10.1158/0008-5472.sabcs-09-1143 ◽

2009 ◽

Author(s):

S. Zaky ◽

X. Zeng ◽

R. O'Regan ◽

T. Liu ◽

H. Saavedra

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Chromosome Instability ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Doxorubicin Resistance

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Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066

International Journal of Oncology ◽

10.3892/ijo.2018.4399 ◽

2018 ◽

Cited By ~ 10

Author(s):

Cong-Cong Cheng ◽

Li-Hong Shi ◽

Xue-Jian Wang ◽

Shu-Xiao Wang ◽

Xiao-Qing Wan ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Inhibitory Effects ◽

Doxorubicin Resistance

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CircUBE2D2 (hsa_circ_0005728) promotes cell proliferation, metastasis and chemoresistance in triple-negative breast cancer by regulating miR-512-3p/CDCA3 axis

Cancer Cell International ◽

10.1186/s12935-020-01547-7 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Dongwei Dou ◽

Xiaoyang Ren ◽

Mingli Han ◽

Xiaodong Xu ◽

Xin Ge ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Circular Rnas ◽

Mechanism Analysis ◽

Western Blot Assay ◽

Doxorubicin Resistance

Abstract Background Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with a bad prognosis. Chemotherapy is still the standard of care for TNBC treatment. Circular RNAs (CircRNAs) have been recently discovered to be closely involved in the initiation and development of human cancers. Herein, we focus our attention on the functions and underlying mechanisms of circUBE2D2 in TNBC progression and chemoresistance. Methods The expression of circUBE2D2, miR-512-3p, and cell division cycle associated 3 (CDCA3) mRNA were determined by qRT-PCR. CCK-8, colony formation, transwell and flow cytometry assays were performed to detect cell proliferation, migration, invasion and apoptosis. Western blot assay was utilized to measure the protein level of CDCA3. RNA pull-down, luciferase reporter and RIP experiments were employed to examine the possible regulatory mechanism of circUBE2D2. Results CircUBE2D2 expression was elevated in TNBC tissues and cells. TNBC patients with high circUBE2D2 expression are inclined to present advanced TNM stage, lymph node metastasis and adverse prognosis. Knockdown of circUBE2D2 repressed cell proliferation, migration and invasion in vitro, and impeded tumor growth in vivo. Moreover, silencing of circUBE2D2 reduced doxorubicin resistance of TNBC cells. In-depth mechanism analysis revealed that circUBE2D2 served as a miRNA sponge to protect CDCA3 from the attack of miR-512-3p. Additionally, the tumor-suppressive effect induced by circUBE2D2 depletion was greatly impaired upon miR512-3p down-regulation or CDCA3 overexpression. Also, depletion of circUBE2D2 decreased the resistance to doxorubicin through regulating miR-512-3p/CDCA3 axis. Conclusion CircUBE2D2 promoted TNBC progression and doxorubicin resistance through acting as a sponge of miR-512-3p to up-regulate CDCA3 expression. Targeting circUBE2D2 combine with doxorubicin might be exploited as a novel therapy for TNBC.

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Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer

Oncogene ◽

10.1038/s41388-021-01720-w ◽

2021 ◽

Vol 40 (16) ◽

pp. 2872-2883

Author(s):

Samantha A. Hutchinson ◽

Alex Websdale ◽

Giorgia Cioccoloni ◽

Hanne Røberg-Larsen ◽

Priscilia Lianto ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Chemotherapy Resistance ◽

Resistance Mechanism ◽

P Glycoprotein ◽

Tumor Tissues ◽

X Receptors ◽

Necessary And Sufficient

AbstractTriple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases.

Download Full-text