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Molecular and Cellular Biochemistry

, Volume 436, Issue 1–2, pp 119–136 | Cite as

Combination of cationic dexamethasone derivative and STAT3 inhibitor (WP1066) for aggressive melanoma: a strategy for repurposing a phase I clinical trial drug

  • Samaresh Sau
  • Sujan Kumar Mondal
  • Sushil K. Kashaw
  • Arun K. Iyer
  • Rajkumar Banerjee
Article

Abstract

Glucocorticoid, such as dexamethasone (Dex) is often used along with chemotherapy to antagonize side effects of chemotherapy. However, sustained use of Dex frequently develops drug resistance in patients. As a strategy to re-induce drug sensitivity, we planned to modify Dex by chemically conjugating it with twin ten carbon aliphatic chain containing cationic lipid. The resultant molecule, DX10, inhibited STAT3 activation through lowering the production of IL-6. To enhance the STAT3 inhibitory effect of DX10, we used WP (a commercially available STAT3 inhibitor) along with DX10. Combination treatment of both significantly inhibited STAT3 activation when compared to either of the individual treatment. The effect of DX10, either in combination or alone, was mediated through glucocorticoid receptor (GR), thereby repurposing the role of GR in the context of p-STAT3 inhibition-mediated cancer treatment. Cellular viability study proved the synergistic effect of WP and DX10. Further, combination treatment led to induction of early stage of apoptosis and cell cycle arrest. In vivo melanoma tumor regression study confirmed the enhanced anti-tumor activity of co-treatment over individual treatment of DX10 or WP. Thus, together our result demonstrates that DX10 may be used in combination therapy with STAT3 inhibitor like WP for combating cancer with constitutively active STAT3.

Graphical abstract

Keywords

Glucocorticoid receptor Dexamethasone derivative STAT3 inhibition Drug sensitization Repurposing WP1066 

Notes

Acknowledgements

SS and SKM thank Council of Scientific and Industrial Research (CSIR), Government of India, New Delhi for their doctoral research fellowships. RB acknowledges financial assistance from CSIR Network Project Grant [CSC0302, BSC0123], Govt. of India.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

Supplementary material

11010_2017_3084_MOESM1_ESM.docx (1.3 mb)
Supplementary material 1 (DOCX 1330 kb)

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Biomaterials GroupCSIR-Indian Institute of Chemical TechnologyHyderabadIndia
  2. 2.Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health SciencesWayne State UniversityDetroitUSA
  3. 3.Academy of Scientific and Innovative Research (AcSIR)Training and Development ComplexChennaiIndia
  4. 4.Department of Pharmaceutical SciencesDr. Harisingh Gour UniversitySagarIndia
  5. 5.Molecular Therapeutics Program, Barbara Ann Karmanos Cancer InstituteWayne State University, School of MedicineDetroitUSA

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