Targeting aberrant replication and DNA repair events for treating breast cancers

Subapriya Rajamanickam; Jun Hyoung Park; Panneerdoss Subbarayalu; Santosh Timilsina; Kaitlyn Bates; Pooja Yadav; Saif S.R. Nirzhor; Vijay Eedunuri; Tabrez A. Mohammad; Kwang Hwa Jung; Benjamin Onyeagucha; Nourhan Abdelfattah; Raymond Benevides; Grace Lee; Yidong Chen; Ratna Vadlamudi; Andrew Brenner; Virginia Kaklamani; Ismail Jatoi; John Kuhn; Robert Hromas; Yogesh K. Gupta; Benny A. Kaipparettu; Jack L. Arbiser; Manjeet K. Rao

doi:10.1038/s42003-022-03413-w

Targeting aberrant replication and DNA repair events for treating breast cancers

Subapriya Rajamanickam, Jun Hyoung Park, Panneerdoss Subbarayalu, Santosh Timilsina, Kaitlyn Bates, Pooja Yadav, Saif S.R. Nirzhor, Vijay Eedunuri, Tabrez A. Mohammad, Kwang Hwa Jung, Benjamin Onyeagucha, Nourhan Abdelfattah, Raymond Benevides, Grace Lee, Yidong Chen, Ratna Vadlamudi, Andrew Brenner, Virginia Kaklamani, Ismail Jatoi, John KuhnRobert Hromas, Yogesh K. Gupta, Benny A. Kaipparettu, Jack L. Arbiser, Manjeet K. Rao

Resultado de la investigación: Article › revisión exhaustiva

Resumen

The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.

Idioma original	English (US)
Número de artículo	493
Publicación	Communications Biology
Volumen	5
N.º	1
DOI	https://doi.org/10.1038/s42003-022-03413-w
Estado	Published - dic 2022

ASJC Scopus subject areas

Medicine (miscellaneous)
Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)

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10.1038/s42003-022-03413-w

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Rajamanickam, S., Park, J. H., Subbarayalu, P., Timilsina, S., Bates, K., Yadav, P., Nirzhor, S. S. R., Eedunuri, V., Mohammad, T. A., Jung, K. H., Onyeagucha, B., Abdelfattah, N., Benevides, R., Lee, G., Chen, Y., Vadlamudi, R., Brenner, A., Kaklamani, V., Jatoi, I., ... Rao, M. K. (2022). Targeting aberrant replication and DNA repair events for treating breast cancers. Communications Biology, 5(1), [493]. https://doi.org/10.1038/s42003-022-03413-w

Rajamanickam, S, Park, JH, Subbarayalu, P, Timilsina, S, Bates, K, Yadav, P, Nirzhor, SSR, Eedunuri, V, Mohammad, TA, Jung, KH, Onyeagucha, B, Abdelfattah, N, Benevides, R, Lee, G, Chen, Y , Vadlamudi, R , Brenner, A , Kaklamani, V , Jatoi, I, Kuhn, J, Hromas, R , Gupta, YK, Kaipparettu, BA, Arbiser, JL & Rao, MK 2022, 'Targeting aberrant replication and DNA repair events for treating breast cancers', Communications Biology, vol. 5, n.º 1, 493. https://doi.org/10.1038/s42003-022-03413-w

@article{57aab8b06fd24405983b879db32cc373,

title = "Targeting aberrant replication and DNA repair events for treating breast cancers",

abstract = "The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.",

author = "Subapriya Rajamanickam and Park, {Jun Hyoung} and Panneerdoss Subbarayalu and Santosh Timilsina and Kaitlyn Bates and Pooja Yadav and Nirzhor, {Saif S.R.} and Vijay Eedunuri and Mohammad, {Tabrez A.} and Jung, {Kwang Hwa} and Benjamin Onyeagucha and Nourhan Abdelfattah and Raymond Benevides and Grace Lee and Yidong Chen and Ratna Vadlamudi and Andrew Brenner and Virginia Kaklamani and Ismail Jatoi and John Kuhn and Robert Hromas and Gupta, {Yogesh K.} and Kaipparettu, {Benny A.} and Arbiser, {Jack L.} and Rao, {Manjeet K.}",

note = "Funding Information: We thank UTHSCSA Genome Sequencing and GCCRI Bioinformatics core facilities for performing microarray and bioinformatics analyses, respectively. We thank Hung I Harry Chen for microarray data analysis. Carbazole blue is protected by US patent # US20130338207A1. We thank Edward Favours for helping with orthotopic and short- and long-term toxicity experiments. We thank Dr. Maria Jasin and Dr. Jeremy Stark for DR-GFP integrated U2OS cells and the pCAGGS vector with I-SceI/GFP. We thank Karen P. Klein (Clarus Editorial Services; https://www.claruseditorialservices.com/ ) for editing. Rao MK is supported by NIH (NCI) Grants R01CA179120-01A1 and R01CA239227-A1. Rao MK and Gupta YK are supported by CPRIT grant RP200110. Chen Y is supported by CPRIT Core Grant RP16073. Chen Y and Rao MK are supported by NCI P30 grant CA054174. B.A.K. is supported by R01CA234479. Timilsina S is supported by NCI T32 grant CA148724. The BCM Patient-derived Xenograft and Advanced In Vivo Models Core is supported by institutional funding from both the Advanced Technology Cores and the Dan L. Duncan Cancer Center (P30 Cancer Center Support Grant NCI-CA125123) and a Core Facility grant from the Cancer Prevention and Research Institute of Texas (CPRIT Core Facilities Support Grant RP170691). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s42003-022-03413-w",

language = "English (US)",

volume = "5",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer Nature",

number = "1",

}

TY - JOUR

T1 - Targeting aberrant replication and DNA repair events for treating breast cancers

AU - Rajamanickam, Subapriya

AU - Park, Jun Hyoung

AU - Subbarayalu, Panneerdoss

AU - Timilsina, Santosh

AU - Bates, Kaitlyn

AU - Yadav, Pooja

AU - Nirzhor, Saif S.R.

AU - Eedunuri, Vijay

AU - Mohammad, Tabrez A.

AU - Jung, Kwang Hwa

AU - Onyeagucha, Benjamin

AU - Abdelfattah, Nourhan

AU - Benevides, Raymond

AU - Lee, Grace

AU - Chen, Yidong

AU - Vadlamudi, Ratna

AU - Brenner, Andrew

AU - Kaklamani, Virginia

AU - Jatoi, Ismail

AU - Kuhn, John

AU - Hromas, Robert

AU - Gupta, Yogesh K.

AU - Kaipparettu, Benny A.

AU - Arbiser, Jack L.

AU - Rao, Manjeet K.

N1 - Funding Information: We thank UTHSCSA Genome Sequencing and GCCRI Bioinformatics core facilities for performing microarray and bioinformatics analyses, respectively. We thank Hung I Harry Chen for microarray data analysis. Carbazole blue is protected by US patent # US20130338207A1. We thank Edward Favours for helping with orthotopic and short- and long-term toxicity experiments. We thank Dr. Maria Jasin and Dr. Jeremy Stark for DR-GFP integrated U2OS cells and the pCAGGS vector with I-SceI/GFP. We thank Karen P. Klein (Clarus Editorial Services; https://www.claruseditorialservices.com/ ) for editing. Rao MK is supported by NIH (NCI) Grants R01CA179120-01A1 and R01CA239227-A1. Rao MK and Gupta YK are supported by CPRIT grant RP200110. Chen Y is supported by CPRIT Core Grant RP16073. Chen Y and Rao MK are supported by NCI P30 grant CA054174. B.A.K. is supported by R01CA234479. Timilsina S is supported by NCI T32 grant CA148724. The BCM Patient-derived Xenograft and Advanced In Vivo Models Core is supported by institutional funding from both the Advanced Technology Cores and the Dan L. Duncan Cancer Center (P30 Cancer Center Support Grant NCI-CA125123) and a Core Facility grant from the Cancer Prevention and Research Institute of Texas (CPRIT Core Facilities Support Grant RP170691). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.

AB - The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.

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U2 - 10.1038/s42003-022-03413-w

DO - 10.1038/s42003-022-03413-w

M3 - Article

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AN - SCOPUS:85130759764

SN - 2399-3642

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JO - Communications Biology

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ER -

Targeting aberrant replication and DNA repair events for treating breast cancers

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