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Strigolactone Analogs: Two New Potential Bioactiphores for Glioblastoma.

ABSTRACT: Strigolactones (SLs), carotenoid-derived phytohormones, control the plant response and signaling pathways for stressful conditions. In addition, they impact numerous cellular processes in mammalians and present new scaffolds for various biomedical applications. Recent studies demonstrated that SLs possess potent antitumor activity against several cancer cells. Herein, we sought to elucidate the inhibitory effects of SL analogs on the growth and survival of human brain tumor cell lines. Among four tested SLs, we showed for the first time that two lead bioactiphores, indanone-derived SL and EGO10, can inhibit cancer cell proliferation, induce apoptosis, and induce G1 cell cycle arrest at low concentrations. SL analogs were marked by increased expression of Bax/Caspase-3 genes and downregulation of Bcl-2. In silico studies were conducted to identify drug-likeness, blood-brain barrier penetrating properties, and molecular docking with Bcl-2 protein. Taken together, this study indicates that SLs may be promising antiglioma agents, presenting novel pharmacophores for further preclinical and clinical assessment.

SUBMITTER: Antika G

PROVIDER: S-EPMC8895406 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Strigolactone Analogs: Two New Potential Bioactiphores for Glioblastoma.

Antika Gizem G Cinar Zeynep Özlem ZÖ Seçen Esma E Özbil Mehmet M Tokay Esra E Köçkar Feray F Prandi Cristina C Tumer Tugba Boyunegmez TB

ACS chemical neuroscience 20220209 5

Strigolactones (SLs), carotenoid-derived phytohormones, control the plant response and signaling pathways for stressful conditions. In addition, they impact numerous cellular processes in mammalians and present new scaffolds for various biomedical applications. Recent studies demonstrated that SLs possess potent antitumor activity against several cancer cells. Herein, we sought to elucidate the inhibitory effects of SL analogs on the growth and survival of human brain tumor cell lines. Among fou ...[more]

PMID: 35138812

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Project description:Root parasitic plants such as Striga and Orobanche cause significant damage on crop production, particularly in sub-Saharan Africa. Their seeds germinate by sensing host root-derived signaling molecules called strigolactones (SLs). SL mimics can be used as suicidal germination inducers for root parasitic plants. Previous attempts to develop such chemicals have revealed that the methylbutenolide ring (D-ring), a common substructure in all the naturally occurring SLs, is critical for SL agonistic activity, suggesting that it should be possible to generate new SL mimics simply by coupling a D-ring with another molecule. Because structural information regarding SLs and their receptor interaction is still limited, such an approach might be an effective strategy to develop new potent SL agonists. Here, we report development of a series of new SL analogs derived from cinnamic acid (CA), the basis of a class of phenylpropanoid natural products that occur widely in plants. CA has an aromatic ring and a double-bond side-chain structure, which are advantageous for preparing structurally diverse derivatives. We prepared SL analogs from cis and trans configuration CA, and found that all the cis-CA-derived SL analogs had stronger activities as seed germination inducers for the root parasitic plants, Orobanche minor and Striga hermonthica, compared with the corresponding trans-CA-derived analogs. Moreover, introduction of a substitution at the C-4 position increased the germination-stimulating activity. We also found that the SL analogs derived from cis-CA were able to interact directly with SL receptor proteins more effectively than the analogs derived from trans-CA. The cis isomer of CA was previously reported to have a growth promoting effect on non-parasitic plants such as Arabidopsis. We found that SL analogs derived from cis-CA also showed growth promoting activity toward Arabidopsis, suggesting that these new SL agonists might be useful not only as suicidal germination inducers for root parasitic weeds, but also as plant growth promoters for the host plants.

Project description:Strigolactones regulate shoot branching and many aspects of plant growth, development, and allelopathy. Strigolactones are often discussed alongside auxin because they work together to inhibit shoot branching. However, the roles and mechanisms of strigolactones and how they act independently of auxin are still elusive. Additionally, there is still much in general to be discovered about the network of molecular regulators and their interactions in response to strigolactones. Here, we conducted an experiment in Arabidopsis with physiological treatments and strigolactone mutants to determine transcriptional pathways associated with strigolactones. The three physiological treatments included shoot tip removal with and without auxin treatment and treatment of intact plants with the auxin transport inhibitor, N-1-naphthylphthalamic acid (NPA). We identified the glucosinolate biosynthesis pathway as being upregulated across strigolactone mutants indicating strigolactone-glucosinolate crosstalk. Additionally, strigolactone application cannot restore the highly branched phenotype observed in glucosinolate biosynthesis mutants, placing glucosinolate biosynthesis downstream of strigolactone biosynthesis. Oxidative stress genes were enriched across the experiment suggesting that this process is mediated through multiple hormones. Here, we also provide evidence supporting non-auxin-mediated, negative feedback on strigolactone biosynthesis. Increases in strigolactone biosynthesis gene expression seen in strigolactone mutants could not be fully restored by auxin. By contrast, auxin could fully restore auxin-responsive gene expression increases, but not sugar signaling-related gene expression. Our data also point to alternative roles of the strigolactone biosynthesis genes and potential new signaling functions of strigolactone precursors. In this study, we identify a strigolactone-specific regulation of glucosinolate biosynthesis genes indicating that the two are linked and may work together in regulating stress and shoot ranching responses in Arabidopsis. Additionally, we provide evidence for non-auxinmediated feedback on strigolactone biosynthesis and discuss this in the context of sugar signaling.

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Strigolactone Analogs: Two New Potential Bioactiphores for Glioblastoma.

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Strigolactone Analogs: Two New Potential Bioactiphores for Glioblastoma.

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