Theranostics 2020; 10(23):10394-10414. doi:10.7150/thno.48675 This issue Cite

Research Paper

Recognition of G-quadruplex topology through hybrid binding with implications in cancer theranostics

Yelisetty Venkata Suseela1, Pardhasaradhi Satha1, N. Arul Murugan2, Thimmaiah Govindaraju1✉

1. Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O., Bengaluru 560064, Karnataka, India.
2. Department of Theoretical Chemistry and Biology, KTH Royal Institute of Technology, S-106 91, Stockholm, Sweden.

Citation:
Suseela YV, Satha P, Murugan NA, Govindaraju T. Recognition of G-quadruplex topology through hybrid binding with implications in cancer theranostics. Theranostics 2020; 10(23):10394-10414. doi:10.7150/thno.48675. https://www.thno.org/v10p10394.htm
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Abstract

Graphic abstract

The selective recognition and imaging of oncogene specific G-quadruplex (GQ) structures holds great promise in the development of diagnostic therapy (theranostics) for cancer and has been challenging due to their structural dynamics and diversity. We report selective recognition of GQ by a small molecule through unique hybrid loop stacking and groove binding mode with turn on far-red fluorescence response and anticancer activity demonstrating the potential implications for GQ-targeted cancer theranostics.

Methods: Biophysical investigation reveal the turn on far-red emission property of TGP18 for selective recognition of GQ. In cellulo studies including DNA damage and oxidative stress evaluation guided us to perform in vitro (3D spheroid) and in vivo (xenograft mice model) anti-cancer activity, and tumor tissue imaging to assess the theranostic potential of TGP18.

Results: Neocuproine-based far-red turn on fluorescence probe TGP18 shows GQ-to-duplex selectivity and specifically recognizes BCL-2 GQ with high affinity through a unique hybrid binding mode involving loop-stacking and groove interactions. Our study reveals that the selective recognition originating from the distinct loop structure of GQ that alters the overall probe interaction and binding affinity. TGP18 binding to anti-apoptotic BCL-2 GQ ablates the pro-survival function and elicit anti-cancer activity by inducing apoptosis in cancer cells. We deciphered that inhibition of BCL-2 transcription synergized with signaling cascade of nucleolar stress, DNA damage and oxidative stress in triggering apoptosis signaling pathway.

Conclusion: Intervention of GQ mediated lethality by TGP18 has translated into anti-cancer activity in both in vitro 3D spheroid culture and in vivo xenograft models of lung and breast cancer with superior efficacy for the former. In vivo therapeutic efficacy supplemented with tumor 3D spheroid and tissue imaging potential define the role of TGP18 in GQ-targeted cancer theranostics.

Keywords: G-quadruplex, hybrid binding, far-red turn on fluorescence, anti-cancer activity, theranostics


Citation styles

APA
Suseela, Y.V., Satha, P., Murugan, N.A., Govindaraju, T. (2020). Recognition of G-quadruplex topology through hybrid binding with implications in cancer theranostics. Theranostics, 10(23), 10394-10414. https://doi.org/10.7150/thno.48675.

ACS
Suseela, Y.V.; Satha, P.; Murugan, N.A.; Govindaraju, T. Recognition of G-quadruplex topology through hybrid binding with implications in cancer theranostics. Theranostics 2020, 10 (23), 10394-10414. DOI: 10.7150/thno.48675.

NLM
Suseela YV, Satha P, Murugan NA, Govindaraju T. Recognition of G-quadruplex topology through hybrid binding with implications in cancer theranostics. Theranostics 2020; 10(23):10394-10414. doi:10.7150/thno.48675. https://www.thno.org/v10p10394.htm

CSE
Suseela YV, Satha P, Murugan NA, Govindaraju T. 2020. Recognition of G-quadruplex topology through hybrid binding with implications in cancer theranostics. Theranostics. 10(23):10394-10414.

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