Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats
The nonsteroidal anti-inflammatory drug (NSAID) sulindac demonstrates attractive anticancer activity, but the toxicity resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins precludes its long-term, high dose use in the clinic for cancer preven...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/3/646 |
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| author | Heather N. Tinsley Bini Mathew Xi Chen Yulia Y. Maxuitenko Nan Li Whitney M. Lowe Jason D. Whitt Wei Zhang Bernard D. Gary Adam B. Keeton William E. Grizzle Clinton J. Grubbs Robert C. Reynolds Gary A. Piazza |
| author_facet | Heather N. Tinsley Bini Mathew Xi Chen Yulia Y. Maxuitenko Nan Li Whitney M. Lowe Jason D. Whitt Wei Zhang Bernard D. Gary Adam B. Keeton William E. Grizzle Clinton J. Grubbs Robert C. Reynolds Gary A. Piazza |
| author_sort | Heather N. Tinsley |
| collection | DOAJ |
| description | The nonsteroidal anti-inflammatory drug (NSAID) sulindac demonstrates attractive anticancer activity, but the toxicity resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins precludes its long-term, high dose use in the clinic for cancer prevention or treatment. While inflammation is a known tumorigenic driver, evidence suggests that sulindac’s antineoplastic activity is partially or fully independent of its COX inhibitory activity. One COX-independent target proposed for sulindac is cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) isozymes. Sulindac metabolites, i.e., sulfide and sulfone, inhibit cGMP PDE enzymatic activity at concentrations comparable with those associated with cancer cell growth inhibitory activity. Additionally, the cGMP PDE isozymes PDE5 and PDE10 are overexpressed during the early stages of carcinogenesis and appear essential for cancer cell proliferation and survival based on gene silencing experiments. Here, we describe a novel amide derivative of sulindac, sulindac sulfide amide (SSA), which was rationally designed to eliminate COX-inhibitory activity while enhancing cGMP PDE inhibitory activity. SSA was 68-fold and 10-fold less potent than sulindac sulfide (SS) in inhibiting COX-1 and COX-2, respectively, but 10-fold more potent in inhibiting growth and inducing apoptosis in breast cancer cells. The pro-apoptotic activity of SSA was associated with inhibition of cGMP PDE activity, elevation of intracellular cGMP levels, and activation of cGMP-dependent protein kinase (PKG) signaling, as well as the inhibition of β-catenin/Tcf transcriptional activity. SSA displayed promising in vivo anticancer activity, resulting in a 57% reduction in the incidence and a 62% reduction in the multiplicity of tumors in the N-methyl-N-nitrosourea (MNU)-induced model of breast carcinogenesis. These findings provide strong evidence for cGMP/PKG signaling as a target for breast cancer prevention or treatment and the COX-independent anticancer properties of sulindac. Furthermore, this study validates the approach of optimizing off-target effects by reducing the COX-inhibitory activity of sulindac for future targeted drug discovery efforts to enhance both safety and efficacy. |
| first_indexed | 2024-03-11T09:51:31Z |
| format | Article |
| id | doaj.art-dfab5b186fc5443c8d2618c19531dfa9 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:51:31Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-dfab5b186fc5443c8d2618c19531dfa92023-11-16T16:15:10ZengMDPI AGCancers2072-66942023-01-0115364610.3390/cancers15030646Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in RatsHeather N. Tinsley0Bini Mathew1Xi Chen2Yulia Y. Maxuitenko3Nan Li4Whitney M. Lowe5Jason D. Whitt6Wei Zhang7Bernard D. Gary8Adam B. Keeton9William E. Grizzle10Clinton J. Grubbs11Robert C. Reynolds12Gary A. Piazza13Department of Biology Chemistry, Mathematics, and Computer Science, University of Montevallo, Montevallo, AL 35115, USADrug Discovery Division, Southern Research, Birmingham, AL 35205, USADepartment of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USADepartment of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USADepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35205, USADepartment of Biology Chemistry, Mathematics, and Computer Science, University of Montevallo, Montevallo, AL 35115, USADepartment of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USADrug Discovery Division, Southern Research, Birmingham, AL 35205, USADrug Discovery Division, Southern Research, Birmingham, AL 35205, USADepartment of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USADepartment of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USADepartment of Surgery, University of Alabama at Birmingham, Birmingham, AL 35205, USAO’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35205, USADepartment of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USAThe nonsteroidal anti-inflammatory drug (NSAID) sulindac demonstrates attractive anticancer activity, but the toxicity resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins precludes its long-term, high dose use in the clinic for cancer prevention or treatment. While inflammation is a known tumorigenic driver, evidence suggests that sulindac’s antineoplastic activity is partially or fully independent of its COX inhibitory activity. One COX-independent target proposed for sulindac is cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) isozymes. Sulindac metabolites, i.e., sulfide and sulfone, inhibit cGMP PDE enzymatic activity at concentrations comparable with those associated with cancer cell growth inhibitory activity. Additionally, the cGMP PDE isozymes PDE5 and PDE10 are overexpressed during the early stages of carcinogenesis and appear essential for cancer cell proliferation and survival based on gene silencing experiments. Here, we describe a novel amide derivative of sulindac, sulindac sulfide amide (SSA), which was rationally designed to eliminate COX-inhibitory activity while enhancing cGMP PDE inhibitory activity. SSA was 68-fold and 10-fold less potent than sulindac sulfide (SS) in inhibiting COX-1 and COX-2, respectively, but 10-fold more potent in inhibiting growth and inducing apoptosis in breast cancer cells. The pro-apoptotic activity of SSA was associated with inhibition of cGMP PDE activity, elevation of intracellular cGMP levels, and activation of cGMP-dependent protein kinase (PKG) signaling, as well as the inhibition of β-catenin/Tcf transcriptional activity. SSA displayed promising in vivo anticancer activity, resulting in a 57% reduction in the incidence and a 62% reduction in the multiplicity of tumors in the N-methyl-N-nitrosourea (MNU)-induced model of breast carcinogenesis. These findings provide strong evidence for cGMP/PKG signaling as a target for breast cancer prevention or treatment and the COX-independent anticancer properties of sulindac. Furthermore, this study validates the approach of optimizing off-target effects by reducing the COX-inhibitory activity of sulindac for future targeted drug discovery efforts to enhance both safety and efficacy.https://www.mdpi.com/2072-6694/15/3/646nonsteroidal anti-inflammatory drug (NSAID)cyclooxygenase (COX)cyclic guanosine monophosphate (cGMP)phosphodiesterase (PDE)breast cancersulindac |
| spellingShingle | Heather N. Tinsley Bini Mathew Xi Chen Yulia Y. Maxuitenko Nan Li Whitney M. Lowe Jason D. Whitt Wei Zhang Bernard D. Gary Adam B. Keeton William E. Grizzle Clinton J. Grubbs Robert C. Reynolds Gary A. Piazza Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats Cancers nonsteroidal anti-inflammatory drug (NSAID) cyclooxygenase (COX) cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) breast cancer sulindac |
| title | Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats |
| title_full | Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats |
| title_fullStr | Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats |
| title_full_unstemmed | Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats |
| title_short | Novel Non-Cyclooxygenase Inhibitory Derivative of Sulindac Inhibits Breast Cancer Cell Growth In Vitro and Reduces Mammary Tumorigenesis in Rats |
| title_sort | novel non cyclooxygenase inhibitory derivative of sulindac inhibits breast cancer cell growth in vitro and reduces mammary tumorigenesis in rats |
| topic | nonsteroidal anti-inflammatory drug (NSAID) cyclooxygenase (COX) cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE) breast cancer sulindac |
| url | https://www.mdpi.com/2072-6694/15/3/646 |
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