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A combination of novel NSC small molecule inhibitor along with doxorubicin inhibits proliferation of triple-negative breast cancer through metabolic reprogramming

Oncogene volume 41, pages 5076–5091 (2022)Cite this article

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A Correction to this article was published on 09 February 2023

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Abstract

Treatment of patients with triple-negative breast cancer (TNBC) has been challenging due to the absence of well-defined molecular targets and the highly invasive and proliferative nature of TNBC cells. Current treatments against TNBC have shown little promise due to high recurrence rate in patients. Consequently, there is a pressing need for novel and efficacious therapies against TNBC. Here, we report the discovery of a novel small molecule inhibitor (NSC33353) with potent anti-tumor activity against TNBC cells. The anti-proliferative effects of this small molecule inhibitor were determined using 2D and 3D cell proliferation assays. We found that NSC33353 significantly reduces the proliferation of TNBC cells in these assays. Using proteomics, next generation sequencing (NGS), and gene enrichment analysis, we investigated global regulatory pathways affected by this compound in TNBC cells. Proteomics data indicate a significant metabolic reprograming affecting both glycolytic enzymes and energy generation through oxidative phosphorylation. Subsequently, using metabolic (Seahorse) and enzymatic assays, we validated our proteomics and NGS analysis findings. Finally, we showed the inhibitory and anti-tumor effects of this small molecule in vitro and confirmed its inhibitory activity in vivo. Doxorubicin is one of the most effective agents in the treatment of TNBC and resistance to this drug has been a major problem. We show that the combination of NSC33353 and doxorubicin suppresses the growth of TNBC cells synergistically, suggesting that NSC33353 enhances TNBC sensitivity to doxorubicin. In summary, our data indicate that the small molecule inhibitor, NSC33353, exhibits anti-tumor activity in TNBC cells, and works in a synergistic fashion with a well-known chemotherapeutic agent.

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Fig. 1: NSC33353 inhibits breast cancer cell proliferation.
Fig. 2: NSC33353 induces apoptosis in TNBC cells.
Fig. 3: NSC33353 inhibitor suppressed migration and invasion of TNBC cells by inhibiting the EMT pathway.
Fig. 4: GSEA analyses showed that NSC33353-treated TNBC cells demonstrated significantly negative glycolysis and oxidative phosphorylation enrichment compared with controls.
Fig. 5: NSC33353 treatment suppressed glycolysis and OXPHOS in TNBC cells.
Fig. 6: NSC33353 treatment significantly suppressed the TNBC tumor growth and suppressed the lung metastasis in vivo.
Fig. 7: NSC33353 treatment reduced the expression of glycolytic, OXPHOS, EMT, angiogenesis, and proliferation markers in vivo.
Fig. 8: Combined treatment with NSC33353 and doxorubicin induced apoptosis in TNBC cells.

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Funding

This work is supported by funds from LSUHSC School of Medicine, Fred G. Brazda foundation, and from NIH grants P20CA202922, P20GM121288-01, P30GM114732 to JZ.

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Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, Louisiana State University Health Science Center (LSUHSC) School of Medicine, New Orleans, LA, USA

    Hassan Yousefi, Maninder Khosla, Samuel C. Okpechi, David Worthylake & Suresh K. Alahari

  2. Department of Pharmacology and Experimental Therapeutics, Cardiovascular Center of Excellence, Louisiana State University Health Science Center (LSUHSC) School of Medicine, New Orleans, LA, USA

    Lothar Lauterboeck & Qinglin Yang

  3. Stanley S. Scott Cancer Center, LSUHSC, New Orleans, LA, USA

    Jone Garai & Dorota Wyczechowska

  4. Department of Interdisciplinary Oncology and Stanley S. Scott Cancer Center, LSUHSC, New Orleans, LA, USA

    Jovanny Zabaleta

  5. Proteomics Core facility, Louisiana State University Health Science Center (LSUHSC), New Orleans, LA, USA

    Jessie Guidry

  6. Department of Chemistry, Tulane University, New Orleans, LA, USA

    Mohammad Amin Zarandi & Janarthanan Jayawickramarajah

  7. Department of Molecular Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Joseph Kissil

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  1. Hassan Yousefi
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  14. Suresh K. Alahari
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Contributions

Methodology: HY, MK, LL, SO, JGa, MZ, and DWy; Formal analysis: JZ, JGu, DWo and SA; Investigation: JJ, JK, QY, and SA; Original draft preparation: HY, SA; review and editing: SA, DWo, Supervision: SA.

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Correspondence to Suresh K. Alahari.

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Yousefi, H., Khosla, M., Lauterboeck, L. et al. A combination of novel NSC small molecule inhibitor along with doxorubicin inhibits proliferation of triple-negative breast cancer through metabolic reprogramming. Oncogene 41, 5076–5091 (2022). https://doi.org/10.1038/s41388-022-02497-2

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