Consecutive salinomycin treatment reduces doxorubicin resistance of breast tumor cells by diminishing drug efflux pump expression and activity

Hermawan, Adam; Wagner, Ernst; Roidl, Andreas

doi:10.3892/or.2015.4509

Cited by 42 publications

(24 citation statements)

References 46 publications

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“…Such effect was mediated by an increase in DNA damage and a reduction in the expression of p21 . Furthermore, pretreatment of breast cancer cells with SAL increases their sensitivity to DXR by decreasing drug efflux pumps expression and activity . In agreement with these findings, we observed that a non‐cytotoxic concentration of SAL significantly increased the cytotoxic effects of DXR on CS spheroids.…”

Section: Discussionsupporting

confidence: 86%

Spheroid‐based 3D cell cultures identify salinomycin as a promising drug for the treatment of chondrosarcoma

Perut

Sbrana

Avnet

et al. 2018

Journal Orthopaedic Research

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Chondrosarcoma (CS) is a cartilage malignancy of adulthood that is treated by surgery alone, since chemotherapy is considered ineffective. Unfortunately, a large proportion of patients with CS develop lung metastases, and several die of the disease. In this study, we compared 3D-spheroid cultures and conventional cell monolayer models in order to identify the best way to select anticancer agents that could be effective for the systemic control of CS. Using SW1353 cells, we developed a three-dimensional (3D) in vitro culture model to mimic in vivo features of CS microenvironment and evaluated the efficacy of different drugs to modulate CS cell proliferation and survival in 2D versus 3D-cultures. Doxorubicin (DXR) and cisplatin, that are widely employed in sarcomas, were less effective on 3D-CS spheroids when compared to standard monolayer models, whereas treatment with the ionophore salinomycin (SAL) had a strong cytotoxic effect both on 2D and 3D-cultures. Furthermore, as demonstrated by the reduced viability and the enhanced DXR nuclear localization, SAL enhanced DXR cytotoxicity in 3D-CS spheroids also at sub-lethal doses. SAL activity on 3D-CS spheroids was mediated by a significant induction of apoptosis via caspase activation. This study demonstrates that preclinical tests significantly differ in monolayer and 3D cultures of CS cells. Using this approach, SAL, alone or, at sub-lethal concentrations, in combination with DXR, represents a promising agent for the systemic treatment of CS. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

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Section: Discussionsupporting

confidence: 86%

Spheroid‐based 3D cell cultures identify salinomycin as a promising drug for the treatment of chondrosarcoma

Perut

Sbrana

Avnet

et al. 2018

Journal Orthopaedic Research

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“…As published previously, long-term single salinomycin treatment, results in the opposite mechanisms, i.e. reduced CSM and increased MDR [35], showing the possibility of salinomycin to counteract the acquired resistance mechanism of single tamoxifen treatment.…”

Section: Discussionmentioning

confidence: 65%

Salinomycin co-treatment enhances tamoxifen cytotoxicity in luminal A breast tumor cells by facilitating lysosomal degradation of receptor tyrosine kinases

et al. 2016

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Luminal A breast cancer is the most common breast cancer subtype which is usually treated with selective estrogen receptor modulators (SERMS) like tamoxifen. Nevertheless, one third of estrogen receptor positive breast cancer patients initially do not respond to endocrine therapy and about 40% of luminal A breast tumors recur in five years. In this study, we investigated an alternative treatment approach by combining tamoxifen and salinomycin in luminal A breast cancer cell lines. We have found that salinomycin induces an additional cytotoxic effect by inhibiting the ligand independent activation of ERα. Thereby salinomycin increases the intracellular calcium level. This leads to a premature fusion of endosomes with lysosomes and thus to the degradation of Egfr family members. Since this process is essential for luminal A breast cancer cells to circumvent tamoxifen treatment, the combination of both drugs induces cytotoxicity in tamoxifen sensitive as well as resistant luminal A breast cancer cell lines.

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“…The IC 50 values were determined to be higher in the PC3, MDA-MB-231 and WM9 cell lines, which are known to have drug-resistant properties (10–12). C54 is a TCM formulation prescribed as pills (‘Hou-Tong-Jie-Du-Wan’) for the treatment of sore throats.…”

Section: Resultsmentioning

confidence: 99%

Pro-inflammatory effect of a traditional Chinese medicine formula with potent anti-cancer activity in vitro impedes tumor inhibitory potential in vivo

Xia

Plachynta

Liu

et al. 2016

Molecular and Clinical Oncology

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Medicinal formulas are a part of the complex discipline of traditional Chinese medicine that has been used for centuries in China and East Asia. These formulas predominantly consist of the extracts isolated from herbal plants, animal parts and medicinal minerals. The present study aimed to investigate the impact of 150 formulas, used as non-prescription drugs in China, on the treatment of cancer. A formula was identified, C54, commonly used to treat sore throats, which exhibited marked growth inhibition in vitro, associated with cell cycle arrest and apoptosis. Cytotoxicity was, in part, due to the ability of C54 to inhibit the expression and function of the transcription factor, Fli-1, leading to marked inhibition of leukemic cell growth in tissue culture. However, when injected into a model of leukemia initiated by Fli-1 activation, C54 only exhibited a limited tumor inhibition. C54 also did not suppress xenograft growth of the breast cancer cell line, MDA-MB-231, orthopedically transplanted into the mammary fat pad of severe combined immunodeficiency (SCID) mice. Notably, splenomegaly and accumulation of inflammatory CD11b+/Gr1+ monocytes were observed in the tumors and spleens of C54-treated mice. As inflammation is known to accelerate tumor progression, this immune response may counteract the cell-autonomous effect of C54, and account for its limited tumor inhibitory effect in vivo. Combining C54 with an anti-inflammatory drug may improve the potency of C54 for treatment of certain cancers. The present study has highlighted the complexity of Chinese medicinal compounds and the need to thoroughly analyze their systemic effects at high concentrations in vivo.

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Consecutive salinomycin treatment reduces doxorubicin resistance of breast tumor cells by diminishing drug efflux pump expression and activity

Cited by 42 publications

References 46 publications

Spheroid‐based 3D cell cultures identify salinomycin as a promising drug for the treatment of chondrosarcoma

Spheroid‐based 3D cell cultures identify salinomycin as a promising drug for the treatment of chondrosarcoma

Salinomycin co-treatment enhances tamoxifen cytotoxicity in luminal A breast tumor cells by facilitating lysosomal degradation of receptor tyrosine kinases

Pro-inflammatory effect of a traditional Chinese medicine formula with potent anti-cancer activity in vitro impedes tumor inhibitory potential in vivo

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