COX-2 Inhibition mediated anti-angiogenic activatable prodrug potentiates cancer therapy in preclinical models

Hyeong Seok Kim, Amit Sharma, Wen Xiu Ren, Jiyou Han, Jong Seung Kim

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Anti-angiogenesis, i.e., blocking the angiogenic pathway, has been considered as an important component in current cancer therapeutic modalities. However, the associated benefits have proven to be modest as tumor angiogenesis and regrowth persist, probably due to other ill-defined complex angiogenic mechanisms. Herein, we developed an indomethacin (IMC) incorporating system to mediate hypoxia responsive prodrug (TA) and diagnostic agent (DA) in cancer theranostic applications. Cyclooxygenase 2 (COX-2) elevated expression in several cancer types is closely associated with severe tumor supporting vascularization factors. Our strategy utilizing COX-2 inhibition augmented the anti-angiogenetic induced hypoxia responsive prodrug activation well. Both in vitro and in vivo results proved that DA and TA exhibited specificity towards COX-2 positive (+ve) HeLa and A549 cancer cell lines and activation under hypoxic conditions. Compared with controls (R1, and anticancer drug SN-38), TA displayed prolonged tumor retention and enhanced therapeutic efficacy in xenograft mouse models at a reduced dosage. Our results significantly highlighted the importance of COX-2 blockade mediated anti-angiogenesis in complementing the hypoxia-responsive drug delivery systems (DDSs) and could to beneficial for the rapid development of more efficacious antitumor therapeutics.

Original languageEnglish
Pages (from-to)63-72
Number of pages10
JournalBiomaterials
Volume185
DOIs
Publication statusPublished - 2018 Dec 1

Fingerprint

Prodrugs
Cyclooxygenase 2
Tumors
irinotecan
Neoplasms
Chemical activation
Therapeutics
Heterografts
Indomethacin
Cells
Drug Delivery Systems
Prostaglandin-Endoperoxide Synthases
Pharmaceutical Preparations
Hypoxia

Keywords

  • Anti-angiogenesis
  • Cancer therapy
  • COX-2
  • Hypoxia
  • Indomethacin

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

COX-2 Inhibition mediated anti-angiogenic activatable prodrug potentiates cancer therapy in preclinical models. / Kim, Hyeong Seok; Sharma, Amit; Ren, Wen Xiu; Han, Jiyou; Kim, Jong Seung.

In: Biomaterials, Vol. 185, 01.12.2018, p. 63-72.

Research output: Contribution to journalArticle

Kim, Hyeong Seok ; Sharma, Amit ; Ren, Wen Xiu ; Han, Jiyou ; Kim, Jong Seung. / COX-2 Inhibition mediated anti-angiogenic activatable prodrug potentiates cancer therapy in preclinical models. In: Biomaterials. 2018 ; Vol. 185. pp. 63-72.
@article{8500dd998cbb4aff89573407a3686c63,
title = "COX-2 Inhibition mediated anti-angiogenic activatable prodrug potentiates cancer therapy in preclinical models",
abstract = "Anti-angiogenesis, i.e., blocking the angiogenic pathway, has been considered as an important component in current cancer therapeutic modalities. However, the associated benefits have proven to be modest as tumor angiogenesis and regrowth persist, probably due to other ill-defined complex angiogenic mechanisms. Herein, we developed an indomethacin (IMC) incorporating system to mediate hypoxia responsive prodrug (TA) and diagnostic agent (DA) in cancer theranostic applications. Cyclooxygenase 2 (COX-2) elevated expression in several cancer types is closely associated with severe tumor supporting vascularization factors. Our strategy utilizing COX-2 inhibition augmented the anti-angiogenetic induced hypoxia responsive prodrug activation well. Both in vitro and in vivo results proved that DA and TA exhibited specificity towards COX-2 positive (+ve) HeLa and A549 cancer cell lines and activation under hypoxic conditions. Compared with controls (R1, and anticancer drug SN-38), TA displayed prolonged tumor retention and enhanced therapeutic efficacy in xenograft mouse models at a reduced dosage. Our results significantly highlighted the importance of COX-2 blockade mediated anti-angiogenesis in complementing the hypoxia-responsive drug delivery systems (DDSs) and could to beneficial for the rapid development of more efficacious antitumor therapeutics.",
keywords = "Anti-angiogenesis, Cancer therapy, COX-2, Hypoxia, Indomethacin",
author = "Kim, {Hyeong Seok} and Amit Sharma and Ren, {Wen Xiu} and Jiyou Han and Kim, {Jong Seung}",
year = "2018",
month = "12",
day = "1",
doi = "10.1016/j.biomaterials.2018.09.006",
language = "English",
volume = "185",
pages = "63--72",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - COX-2 Inhibition mediated anti-angiogenic activatable prodrug potentiates cancer therapy in preclinical models

AU - Kim, Hyeong Seok

AU - Sharma, Amit

AU - Ren, Wen Xiu

AU - Han, Jiyou

AU - Kim, Jong Seung

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Anti-angiogenesis, i.e., blocking the angiogenic pathway, has been considered as an important component in current cancer therapeutic modalities. However, the associated benefits have proven to be modest as tumor angiogenesis and regrowth persist, probably due to other ill-defined complex angiogenic mechanisms. Herein, we developed an indomethacin (IMC) incorporating system to mediate hypoxia responsive prodrug (TA) and diagnostic agent (DA) in cancer theranostic applications. Cyclooxygenase 2 (COX-2) elevated expression in several cancer types is closely associated with severe tumor supporting vascularization factors. Our strategy utilizing COX-2 inhibition augmented the anti-angiogenetic induced hypoxia responsive prodrug activation well. Both in vitro and in vivo results proved that DA and TA exhibited specificity towards COX-2 positive (+ve) HeLa and A549 cancer cell lines and activation under hypoxic conditions. Compared with controls (R1, and anticancer drug SN-38), TA displayed prolonged tumor retention and enhanced therapeutic efficacy in xenograft mouse models at a reduced dosage. Our results significantly highlighted the importance of COX-2 blockade mediated anti-angiogenesis in complementing the hypoxia-responsive drug delivery systems (DDSs) and could to beneficial for the rapid development of more efficacious antitumor therapeutics.

AB - Anti-angiogenesis, i.e., blocking the angiogenic pathway, has been considered as an important component in current cancer therapeutic modalities. However, the associated benefits have proven to be modest as tumor angiogenesis and regrowth persist, probably due to other ill-defined complex angiogenic mechanisms. Herein, we developed an indomethacin (IMC) incorporating system to mediate hypoxia responsive prodrug (TA) and diagnostic agent (DA) in cancer theranostic applications. Cyclooxygenase 2 (COX-2) elevated expression in several cancer types is closely associated with severe tumor supporting vascularization factors. Our strategy utilizing COX-2 inhibition augmented the anti-angiogenetic induced hypoxia responsive prodrug activation well. Both in vitro and in vivo results proved that DA and TA exhibited specificity towards COX-2 positive (+ve) HeLa and A549 cancer cell lines and activation under hypoxic conditions. Compared with controls (R1, and anticancer drug SN-38), TA displayed prolonged tumor retention and enhanced therapeutic efficacy in xenograft mouse models at a reduced dosage. Our results significantly highlighted the importance of COX-2 blockade mediated anti-angiogenesis in complementing the hypoxia-responsive drug delivery systems (DDSs) and could to beneficial for the rapid development of more efficacious antitumor therapeutics.

KW - Anti-angiogenesis

KW - Cancer therapy

KW - COX-2

KW - Hypoxia

KW - Indomethacin

UR - http://www.scopus.com/inward/record.url?scp=85054676252&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054676252&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2018.09.006

DO - 10.1016/j.biomaterials.2018.09.006

M3 - Article

C2 - 30223141

AN - SCOPUS:85054676252

VL - 185

SP - 63

EP - 72

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

ER -