Safe and targeted anticancer efficacy of a novel class of antioxidant-conjugated difluorodiarylidenyl piperidones: Differential cytotoxicity in healthy and cancer cells

Karuppaiyah Selvendiran, Shabnam Ahmed, Alex Dayton, M. Lakshmi Kuppusamy, Mia Tazi, Anna Bratasz, Liyue Tong, Brian K. Rivera, T. Kalai, K. Hideg, Periannan Kuppusamy

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The development of smart anticancer drugs that can selectively kill cancer cells while sparing the surrounding healthy tissues/cells is of paramount importance for safe and effective cancer therapy. We report a novel class of bifunctional compounds based on diarylidenyl piperidone (DAP) conjugated to an N-hydroxypyrroline (NOH; a nitroxide precursor) group. We hypothesized that the DAP would have cytotoxic (anticancer) activity, whereas the NOH moiety would function as a tissue-specific modulator (antioxidant) of cytotoxicity. The study used four DAPs, namely H-4073 and H-4318 without NOH and HO-3867 and HO-4200 with NOH substitution. The goal of the study was to evaluate the proof-of-concept anticancer-versus. -antioxidant efficacy of the DAPs using a number of cancerous (breast, colon, head and neck, liver, lung, ovarian, and prostate cancer) and noncancerous (smooth muscle, aortic endothelial, and ovarian surface epithelial) human cell lines. Cytotoxicity was determined using an MTT-based cell viability assay. All four compounds induced significant loss of cell viability in cancer cells, whereas HO-3867 and HO-4200 showed significantly less cytotoxicity in noncancerous cells. EPR measurements showed a metabolic conversion of the N-hydroxylamine function to nitroxide with significantly higher levels of the metabolite and superoxide radical-scavenging (antioxidant) activity in noncancerous cells compared to cancer cells. Western blot analysis showed that the DAP-induced growth arrest and apoptosis in cancer cells were mediated by inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues and induction of apoptotic markers of cleaved caspase-3 and PARP. The results suggest that the antioxidant-conjugated DAPs will be useful as safe and effective anticancer agents for cancer therapy.

Original languageEnglish
Pages (from-to)1228-1235
Number of pages8
JournalFree Radical Biology and Medicine
Volume48
Issue number9
DOIs
Publication statusPublished - May 2010

Fingerprint

Piperidones
Cytotoxicity
Antioxidants
Cells
Neoplasms
Cell Survival
Tissue
Hydroxylamine
Phosphorylation
Scavenging
Liver Neoplasms
Head and Neck Neoplasms
Metabolites
Superoxides
Caspase 3
Liver
Antineoplastic Agents
Ovarian Neoplasms
Modulators
Smooth Muscle

Keywords

  • Curcumin
  • Diarylidenyl piperidone
  • Free radicals
  • Human cancer cell line
  • Nitroxide
  • Ovarian cancer
  • STAT3

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Safe and targeted anticancer efficacy of a novel class of antioxidant-conjugated difluorodiarylidenyl piperidones : Differential cytotoxicity in healthy and cancer cells. / Selvendiran, Karuppaiyah; Ahmed, Shabnam; Dayton, Alex; Kuppusamy, M. Lakshmi; Tazi, Mia; Bratasz, Anna; Tong, Liyue; Rivera, Brian K.; Kalai, T.; Hideg, K.; Kuppusamy, Periannan.

In: Free Radical Biology and Medicine, Vol. 48, No. 9, 05.2010, p. 1228-1235.

Research output: Contribution to journalArticle

Selvendiran, Karuppaiyah ; Ahmed, Shabnam ; Dayton, Alex ; Kuppusamy, M. Lakshmi ; Tazi, Mia ; Bratasz, Anna ; Tong, Liyue ; Rivera, Brian K. ; Kalai, T. ; Hideg, K. ; Kuppusamy, Periannan. / Safe and targeted anticancer efficacy of a novel class of antioxidant-conjugated difluorodiarylidenyl piperidones : Differential cytotoxicity in healthy and cancer cells. In: Free Radical Biology and Medicine. 2010 ; Vol. 48, No. 9. pp. 1228-1235.
@article{b2f2fec81a544f9185496c682134ffda,
title = "Safe and targeted anticancer efficacy of a novel class of antioxidant-conjugated difluorodiarylidenyl piperidones: Differential cytotoxicity in healthy and cancer cells",
abstract = "The development of smart anticancer drugs that can selectively kill cancer cells while sparing the surrounding healthy tissues/cells is of paramount importance for safe and effective cancer therapy. We report a novel class of bifunctional compounds based on diarylidenyl piperidone (DAP) conjugated to an N-hydroxypyrroline (NOH; a nitroxide precursor) group. We hypothesized that the DAP would have cytotoxic (anticancer) activity, whereas the NOH moiety would function as a tissue-specific modulator (antioxidant) of cytotoxicity. The study used four DAPs, namely H-4073 and H-4318 without NOH and HO-3867 and HO-4200 with NOH substitution. The goal of the study was to evaluate the proof-of-concept anticancer-versus. -antioxidant efficacy of the DAPs using a number of cancerous (breast, colon, head and neck, liver, lung, ovarian, and prostate cancer) and noncancerous (smooth muscle, aortic endothelial, and ovarian surface epithelial) human cell lines. Cytotoxicity was determined using an MTT-based cell viability assay. All four compounds induced significant loss of cell viability in cancer cells, whereas HO-3867 and HO-4200 showed significantly less cytotoxicity in noncancerous cells. EPR measurements showed a metabolic conversion of the N-hydroxylamine function to nitroxide with significantly higher levels of the metabolite and superoxide radical-scavenging (antioxidant) activity in noncancerous cells compared to cancer cells. Western blot analysis showed that the DAP-induced growth arrest and apoptosis in cancer cells were mediated by inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues and induction of apoptotic markers of cleaved caspase-3 and PARP. The results suggest that the antioxidant-conjugated DAPs will be useful as safe and effective anticancer agents for cancer therapy.",
keywords = "Curcumin, Diarylidenyl piperidone, Free radicals, Human cancer cell line, Nitroxide, Ovarian cancer, STAT3",
author = "Karuppaiyah Selvendiran and Shabnam Ahmed and Alex Dayton and Kuppusamy, {M. Lakshmi} and Mia Tazi and Anna Bratasz and Liyue Tong and Rivera, {Brian K.} and T. Kalai and K. Hideg and Periannan Kuppusamy",
year = "2010",
month = "5",
doi = "10.1016/j.freeradbiomed.2010.02.009",
language = "English",
volume = "48",
pages = "1228--1235",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "9",

}

TY - JOUR

T1 - Safe and targeted anticancer efficacy of a novel class of antioxidant-conjugated difluorodiarylidenyl piperidones

T2 - Differential cytotoxicity in healthy and cancer cells

AU - Selvendiran, Karuppaiyah

AU - Ahmed, Shabnam

AU - Dayton, Alex

AU - Kuppusamy, M. Lakshmi

AU - Tazi, Mia

AU - Bratasz, Anna

AU - Tong, Liyue

AU - Rivera, Brian K.

AU - Kalai, T.

AU - Hideg, K.

AU - Kuppusamy, Periannan

PY - 2010/5

Y1 - 2010/5

N2 - The development of smart anticancer drugs that can selectively kill cancer cells while sparing the surrounding healthy tissues/cells is of paramount importance for safe and effective cancer therapy. We report a novel class of bifunctional compounds based on diarylidenyl piperidone (DAP) conjugated to an N-hydroxypyrroline (NOH; a nitroxide precursor) group. We hypothesized that the DAP would have cytotoxic (anticancer) activity, whereas the NOH moiety would function as a tissue-specific modulator (antioxidant) of cytotoxicity. The study used four DAPs, namely H-4073 and H-4318 without NOH and HO-3867 and HO-4200 with NOH substitution. The goal of the study was to evaluate the proof-of-concept anticancer-versus. -antioxidant efficacy of the DAPs using a number of cancerous (breast, colon, head and neck, liver, lung, ovarian, and prostate cancer) and noncancerous (smooth muscle, aortic endothelial, and ovarian surface epithelial) human cell lines. Cytotoxicity was determined using an MTT-based cell viability assay. All four compounds induced significant loss of cell viability in cancer cells, whereas HO-3867 and HO-4200 showed significantly less cytotoxicity in noncancerous cells. EPR measurements showed a metabolic conversion of the N-hydroxylamine function to nitroxide with significantly higher levels of the metabolite and superoxide radical-scavenging (antioxidant) activity in noncancerous cells compared to cancer cells. Western blot analysis showed that the DAP-induced growth arrest and apoptosis in cancer cells were mediated by inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues and induction of apoptotic markers of cleaved caspase-3 and PARP. The results suggest that the antioxidant-conjugated DAPs will be useful as safe and effective anticancer agents for cancer therapy.

AB - The development of smart anticancer drugs that can selectively kill cancer cells while sparing the surrounding healthy tissues/cells is of paramount importance for safe and effective cancer therapy. We report a novel class of bifunctional compounds based on diarylidenyl piperidone (DAP) conjugated to an N-hydroxypyrroline (NOH; a nitroxide precursor) group. We hypothesized that the DAP would have cytotoxic (anticancer) activity, whereas the NOH moiety would function as a tissue-specific modulator (antioxidant) of cytotoxicity. The study used four DAPs, namely H-4073 and H-4318 without NOH and HO-3867 and HO-4200 with NOH substitution. The goal of the study was to evaluate the proof-of-concept anticancer-versus. -antioxidant efficacy of the DAPs using a number of cancerous (breast, colon, head and neck, liver, lung, ovarian, and prostate cancer) and noncancerous (smooth muscle, aortic endothelial, and ovarian surface epithelial) human cell lines. Cytotoxicity was determined using an MTT-based cell viability assay. All four compounds induced significant loss of cell viability in cancer cells, whereas HO-3867 and HO-4200 showed significantly less cytotoxicity in noncancerous cells. EPR measurements showed a metabolic conversion of the N-hydroxylamine function to nitroxide with significantly higher levels of the metabolite and superoxide radical-scavenging (antioxidant) activity in noncancerous cells compared to cancer cells. Western blot analysis showed that the DAP-induced growth arrest and apoptosis in cancer cells were mediated by inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues and induction of apoptotic markers of cleaved caspase-3 and PARP. The results suggest that the antioxidant-conjugated DAPs will be useful as safe and effective anticancer agents for cancer therapy.

KW - Curcumin

KW - Diarylidenyl piperidone

KW - Free radicals

KW - Human cancer cell line

KW - Nitroxide

KW - Ovarian cancer

KW - STAT3

UR - http://www.scopus.com/inward/record.url?scp=77950338477&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950338477&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2010.02.009

DO - 10.1016/j.freeradbiomed.2010.02.009

M3 - Article

C2 - 20156552

AN - SCOPUS:77950338477

VL - 48

SP - 1228

EP - 1235

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 9

ER -