Universität zu Köln

Reimche, Irene ORCID: 0000-0001-8027-7672, Yu, Haiqian, Ariantari, Ni Putu, Liu, Zhen, Merkens, Kay ORCID: 0000-0003-0753-2117, Rotfuss, Stella, Peter, Karin, Jungwirth, Ute, Bauer, Nadine ORCID: 0000-0002-4483-4205, Kiefer, Friedemann ORCID: 0000-0002-3002-8237, Neudoerfl, Joerg-Martin, Schmalz, Hans-Guenther, Proksch, Peter and Teusch, Nicole (2022). Phenanthroindolizidine Alkaloids Isolated from Tylophora ovata as Potent Inhibitors of Inflammation, Spheroid Growth, and Invasion of Triple-Negative Breast Cancer. Int. J. Mol. Sci., 23 (18). BASEL: MDPI. ISSN 1422-0067

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Abstract

Triple-negative breast cancer (TNBC), representing the most aggressive form of breast cancer with currently no targeted therapy available, is characterized by an inflammatory and hypoxic tumor microenvironment. To date, a broad spectrum of anti-tumor activities has been reported for phenanthroindolizidine alkaloids (PAs), however, their mode of action in TNBC remains elusive. Thus, we investigated six naturally occurring PAs extracted from the plant Tylophora ovata: O-methyltylophorinidine (1) and its five derivatives tylophorinidine (2), tylophoridicine E (3), 2-demethoxytylophorine (4), tylophoridicine D (5), and anhydrodehydrotylophorinidine (6). In comparison to natural (1) and for more-in depth studies, we also utilized a sample of synthetic O-methyltylophorinidine (1s). Our results indicate a remarkably effective blockade of nuclear factor kappa B (NF kappa B) within 2 h for compounds (1) and (1s) (IC50 = 17.1 +/- 2.0 nM and 3.3 +/- 0.2 nM) that is different from its effect on cell viability within 24 h (IC50 = 13.6 +/- 0.4 nM and 4.2 +/- 1 nM). Furthermore, NF kappa B inhibition data for the additional five analogues indicate a structure-activity relationship (SAR). Mechanistically, NF kappa B is significantly blocked through the stabilization of its inhibitor protein kappa B alpha (I kappa B alpha) under normoxic as well as hypoxic conditions. To better mimic the TNBC microenvironment in vitro, we established a 3D co-culture by combining the human TNBC cell line MDA-MB-231 with primary murine cancer-associated fibroblasts (CAF) and type I collagen. Compound (1) demonstrates superiority against the therapeutic gold standard paclitaxel by diminishing spheroid growth by 40% at 100 nM. The anti-proliferative effect of (1s) is distinct from paclitaxel in that it arrests the cell cycle at the G0/G1 state, thereby mediating a time-dependent delay in cell cycle progression. Furthermore, (1s) inhibited invasion of TNBC monoculture spheroids into a matrigel (R)-based environment at 10 nM. In conclusion, PAs serve as promising agents with presumably multiple target sites to combat inflammatory and hypoxia-driven cancer, such as TNBC, with a different mode of action than the currently applied chemotherapeutic drugs.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Reimche, Irene UNSPECIFIED orcid.org/0000-0001-8027-7672 UNSPECIFIED Yu, Haiqian UNSPECIFIED UNSPECIFIED UNSPECIFIED Ariantari, Ni Putu UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Zhen UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkens, Kay UNSPECIFIED orcid.org/0000-0003-0753-2117 UNSPECIFIED Rotfuss, Stella UNSPECIFIED UNSPECIFIED UNSPECIFIED Peter, Karin UNSPECIFIED UNSPECIFIED UNSPECIFIED Jungwirth, Ute UNSPECIFIED UNSPECIFIED UNSPECIFIED Bauer, Nadine UNSPECIFIED orcid.org/0000-0002-4483-4205 UNSPECIFIED Kiefer, Friedemann UNSPECIFIED orcid.org/0000-0002-3002-8237 UNSPECIFIED Neudoerfl, Joerg-Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmalz, Hans-Guenther UNSPECIFIED UNSPECIFIED UNSPECIFIED Proksch, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Teusch, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-687552
DOI:	10.3390/ijms231810319
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	23
Number:	18
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; CELL-GROWTH; GENE-EXPRESSION; STEM-CELLS; HYPOXIA; HETEROGENEITY; CARCINOMA; ROLES; PERGULARININE; CHEMOTHERAPY Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68755