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Retinoic acid and evernyl-based menadione-triazole hybrid cooperate to induce differentiation of neuroblastoma cells

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Abstract

Neuroblastoma arises when immature neural precursor cells do not mature into specialized cells. Although retinoic acid (RA), a pro-differentiation agent, improves the survival of low-grade neuroblastoma, resistance to retinoic acid is found in high-grade neuroblastoma patients. Histone deacetylases (HDAC) inhibitors induce differentiation and arrest the growth of cancer cells; however, HDAC inhibitors are FDA-approved mostly for liquid tumors. Therefore, combining histone deacetylase (HDAC) inhibitors and retinoic acid can be explored as a strategy to trigger the differentiation of neuroblastoma cells and to overcome resistance to retinoic acid. Based on this rationale, in this study, we linked evernyl group and menadione-triazole motifs to synthesize evernyl-based menadione-triazole hybrids and asked if the hybrids cooperate with retinoic acid to trigger the differentiation of neuroblastoma cells. To answer this question, we treated neuroblastoma cells using evernyl-based menadione-triazole hybrids (6a–6i) or RA or both and examined the differentiation of neuroblastoma cells. Among the hybrids, we found that compound 6b inhibits class-I HDAC activity, induces differentiation, and RA co-treatments increase 6b-induced differentiation of neuroblastoma cells. In addition, 6b reduces cell proliferation, induces expression of differentiation-specific microRNAs leading to N-Myc downregulation, and RA co-treatments enhance the 6b-induced effects. We observed that 6b and RA trigger a switch from glycolysis to oxidative phosphorylation, maintain mitochondrial polarization, and increase oxygen consumption rate. We conclude that in evernyl-based menadione-triazole hybrid, 6b cooperates with RA to induce differentiation of neuroblastoma cells. Based on our results, we suggest that combining RA and 6b can be pursued as therapy for neuroblastoma.

Graphical Abstract

Schematic representation of RA and 6b in inducing differentiation of neuroblastoma cells

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Data Availability

Request for reagents can be directed to N.J. To whom correspondence may be addressed: Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India. Tel.: 91–40-27191857; Fax: 91–40-27191812; E-mail: nishant.iict@gov.in.

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Acknowledgements

J.J.M, S.T.R, and V.K.K.M thank Council of Scientific and Industrial Research, India for the senior research fellowship. H.D. thanks DST-INSPIRE, India for the senior research fellowship. We thank Suresh Y for assistance in Flow cytometry. We thank Director, CSIR-IICT for providing all the required facilities to carry out the work (Ms. No. IICT/Pubs./2021/299).

Funding

This work was supported by grants from the Department of Biotechnology (DBT, GAP-0770), New Delhi, India, to M.P.B and the Council of Scientific and Industrial Research (CSIR-IICT/MLP0068), India, to N.J.

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Authors and Affiliations

  1. Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana State, India

    Jolly Janette Mendonza, Hashnu Dutta, Venkata Krishna Kanth Makani, Nishant Jain & Manika Pal Bhadra

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Jolly Janette Mendonza, Hashnu Dutta, Venkata Krishna Kanth Makani, Venkata Mallavadhani Uppuluri, Nishant Jain & Manika Pal Bhadra

  3. Center for Natural Products and Traditional Knowledge, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana State, India

    Srilakshmi Tirupathamma Reddy & Venkata Mallavadhani Uppuluri

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  1. Jolly Janette Mendonza
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Contributions

Jolly Janette Mendonza: conceptualization; methodology; validation; data curation; writing — original draft; writing — review and editing. Srilakshmi Tirupathamma Reddy, Hashnu Dutta, and Venkata Krishna Kanth Makani: methodology, validation, data curation. Venkata Mallavadhani Uppuluri: supervision, writing — review and editing. Nishant Jain: supervision, writing — review and editing, funding acquisition. Manika Pal Bhadra: supervision, writing — review and editing, conceptualization, investigation, project administration, funding acquisition. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Venkata Mallavadhani Uppuluri, Nishant Jain or Manika Pal Bhadra.

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Highlights

6b is a class-I HDAC inhibitor.

6b and RA increase differentiation of neuroblastoma cells.

6b and RA trigger metabolic switch in neuroblastoma cells.

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Mendonza, J.J., Reddy, S.T., Dutta, H. et al. Retinoic acid and evernyl-based menadione-triazole hybrid cooperate to induce differentiation of neuroblastoma cells. Naunyn-Schmiedeberg's Arch Pharmacol 396, 2651–2665 (2023). https://doi.org/10.1007/s00210-023-02489-3

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