Multitargeting Effects of Calebin A on Malignancy of CRC Cells in Multicellular Tumor Microenvironment

Buhrmann, Constanze; Kunnumakkara, Ajaikumar B.; Kumar, Aviral; Samec, Marek; Kubatka, Peter; Aggarwal, Bharat B.; Shakibaei, Mehdi

doi:10.3389/fonc.2021.650603

Cited by 22 publications

(15 citation statements)

References 78 publications

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“…Therefore, to obtain more information about the underlying mechanism, we screened for NF-kB signaling in this work and found that p65-NF-kB, FAK (downstream of β1-integrin), and cyclin D1 (protein regulating cell cycle progression), strongly and at the same time, caspase-3 (apoptosis) was poorly expressed in TME. In numerous previous publications by our group, we compared the expression of these proteins in the TME of the cell lines also used in this work with a basal control without TME, confirming the notion that the described protein expressions are significantly induced in the TME [30,46,[48][49][50]. In parallel, blocking the β1-integrin receptor by the antibody against β1-integrin but not against other integrin chains, the β5-integrin antibody, or by treatment with the integrin epitope suppressor RGD, but not with RGE peptides, led to inhibition of resveratrol-depressed p65-NF-kB, p-FAK, and cyclin D1 expression, and resveratrolactivated caspase-3.…”

Section: Discussionsupporting

confidence: 84%

Evidence That β1-Integrin Is Required for the Anti-Viability and Anti-Proliferative Effect of Resveratrol in CRC Cells

Brockmueller

Shayan

Shakibaei

2022

IJMS

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The β1-integrin receptor is broadly expressed on tumor and other cells in the tumor microenvironment (TME), and is an unfavorable prognostic factor for cancers. Nature-derived resveratrol has preventive and apoptotic effects on tumors, but whether resveratrol can exert its suppressive actions on TME-induced tumorigenesis through β1-integrin on the surface of CRC cells is still unknown. HCT116 or SW480 cells were exposed to inhibitory antibodies against β1-integrin, bacitracin (selective β1-integrin inhibitor), integrin-binding RGD (Arg-Gly-Asp) peptide, and/or resveratrol. We evaluated the anti-tumor actions and signaling impacts of resveratrol in colorectal cancer (CRC)-TME. We found that resveratrol completely altered the β1-integrin distribution pattern and expression on the surface of CRC cells in TME. Moreover, resveratrol down-regulated CRC cell proliferation, colony formation, viability, and up-regulated apoptosis in a concentration-dependent way. These actions of resveratrol were antagonized mainly by inhibitory antibodies against β1-integrin but not β5-integrin, and by an integrin-binding RGD peptide but not by RGE peptide, and by bacitracin in TME. Similarly, resveratrol-blocked TME-induced p65-NF-kB and its promoted gene markers linked to proliferation (cyclin D1), invasion (focal adhesion kinase, FAK), or apoptosis (caspase-3), were largely abrogated by anti-β1-integrin or RGD peptide, suggesting that β1-integrin is a potential transmission pathway for resveratrol/integrin down-stream signaling in CRC cells. The current results highlight, for the first time, the important gateway role of β1-integrins as signal carriers for resveratrol on the surfaces of HCT116 and SW480 cells, and their functional cooperation for the modulatory effects of resveratrol on TME-promoted tumorigenesis.

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Section: Discussionsupporting

confidence: 84%

Evidence That β1-Integrin Is Required for the Anti-Viability and Anti-Proliferative Effect of Resveratrol in CRC Cells

Brockmueller

Shayan

Shakibaei

2022

IJMS

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“…Previous reports have indicated CBA’s apoptotic, anti-cell proliferation, and anti-inflammatory properties in colorectal cancer cells. 9 Other reports have shown that CBA has a robust antiproliferative effect on NF-kB-mediated cell proliferation in three colorectal cancer cells (HCT-116, RKO, and SW480). 10 Mechanistically, CBA was reported to suppress NF-kB induced by various stimuli in different cell lines by suppressing the direct binding of the NF-κB/p65 subunit essential for NF-kB transactivation and binding to DNA.…”

Section: Discussionmentioning

confidence: 94%

“… 8 It has also been reported to ameliorate obesity or high-fat diet-induced colitis. 9 HPSB has antiproliferative effects on multidrug-resistant human leukemic HL60 and K562 cells. 10 Other studies have also shown that topical treatment with HPSB prevents mouse skin tumorigenesis.…”

Section: Introductionmentioning

confidence: 95%

Augmentation of Docetaxel-Induced Cytotoxicity in Human PC-3 Androgen-Independent Prostate Cancer Cells by Combination With Four Natural Apoptosis-Inducing Anticancer Compounds

Ahmed

Hafiz

Ginkel

et al. 2023

Natural Product Communications

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Docetaxel (DTX) is the treatment of choice for metastatic castration-resistant prostate cancer. However, developing drug resistance is a significant challenge for achieving effective therapy. This study evaluated the anticancer and synergistic effects on DTX of four natural compounds (calebin A, 3′-hydroxypterostilbene, hispolon, and tetrahydrocurcumin) using PC-3 androgen-resistant human prostate cancer cells. We utilized the CellTiter-Glo® luminescent cell viability assay and human PC-3 androgen-independent prostate cancer cells to determine the antiproliferative effects of the four compounds alone and combined with DTX. Cytotoxicity to normal human prostate epithelial cells was tested in parallel using normal immortalized human prostate epithelial cells (RWPE-1). We used cell imaging and quantitative caspase-3 activity to determine whether these compounds induce apoptosis. We also measured the capacity of each drug to inhibit TNF-α-induced NF-kB using a colorimetric assay. Our results showed that all four natural compounds significantly augmented the toxicity of DTX to androgen-resistant PC-3 prostate cancer cells at IC50. Interestingly, when used alone, each of the four compounds had a higher cytotoxic activity to PC-3 than DTX. Mechanistically, these compounds induced apoptosis, which we confirmed by cell imaging and caspase-3 colorimetric assays. Further, when used either alone or combined with DTX, the four test compounds inhibited TNF-α-induced NF-kB production. More significantly, the cytotoxic effects on normal immortalized human prostate epithelial cells were minimal and non-significant, suggesting prostate cancer-specific effects. In conclusion, the combination of DTX with the four test compounds could effectively enhance the anti-prostate cancer activity of DTX. This combination has the added value of reducing the DTX effective concentration. We surmise that calebin A, 3′-hydroxypterostilbene, hispolon, and tetrahydrocurcumin were all excellent drug candidates that produced significant antiproliferative activity when used alone and synergistically enhanced the anticancer effect of DTX. Further in vivo studies using animal models of prostate cancer are needed to confirm our in vitro findings.

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“…The dissolved CRC cells were washed off with Hank's salt solution, wells were replenished with the 3% FBS Frontiers in Pharmacology frontiersin.org cell culture medium, and wound incisions were photographed using a phase contrast Axiovert 40 CFL microscope (Zeiss, Oberkochen, Germany). Now, the trial substances were added for 2 h, and then, the glass plates were located in a 3D-model, as already used previously (Buhrmann et al, 2021b). The 3D-environment was built in 6-well plates with each well containing a small steel bridge on which the CRC-glass plates were placed.…”

Section: Migration Investigationmentioning

confidence: 99%

Calebin A targets the HIF-1α/NF-κB pathway to suppress colorectal cancer cell migration

Brockmueller,

Girisa,

Motallebi

et al. 2023

Front. Pharmacol.

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Background: Hypoxia-inducible factor-1α (HIF-1α) is one of the major tumor-associated transcription factors modulating numerous tumor properties such as tumor cell metabolism, survival, proliferation, angiogenesis, and metastasis. Calebin A (CA), a compound derived from turmeric, is known for its anti-cancer activity through modulation of the NF-κB pathway. However, its impact on HIF-1α in colorectal cancer (CRC) cell migration is unknown.Methods: Human CRC cells (HCT-116) in 3D alginate and monolayer multicellular TME (fibroblasts/T lymphocytes) were subjected to CA or the HIF-1α inhibitor to explore the efficacy of CA on TME-induced inflammation, migration, and tumor malignancy.Results: CA significantly inhibited TME-promoted proliferation and migration of HCT-116 cells, similar to the HIF-1α inhibitor. Colony formation, toluidine blue staining, and immunolabeling showed that CA inhibited the migration of HCT-116 cells partly by inhibiting HIF-1α, which is critical for CRC cell viability, and these observations were confirmed by electron microscopy. In addition, Western blot analysis confirmed that CA inhibited TME-initiated expression of HIF-1α and biomarkers of metastatic factors (such as NF-κB, β1-integrin, and VEGF), and promoted apoptosis (caspase-3), in a manner comparable to the HIF-1α inhibitor. Finally, TME induced a purposeful pairing between HIF-1α and NF-κB, suggesting that the synergistic interplay between the two tumor-associated transcription factors is essential for CRC cell malignancy and migration and that CA silences these factors in tandem.Conclusion: These results shed light on a novel regulatory modulation of CA signaling in CRC cell migration, partially via HIF-1α/NF-κB with potentially relevant implications for cancer therapy.

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Multitargeting Effects of Calebin A on Malignancy of CRC Cells in Multicellular Tumor Microenvironment

Cited by 22 publications

References 78 publications

Evidence That β1-Integrin Is Required for the Anti-Viability and Anti-Proliferative Effect of Resveratrol in CRC Cells

Evidence That β1-Integrin Is Required for the Anti-Viability and Anti-Proliferative Effect of Resveratrol in CRC Cells

Augmentation of Docetaxel-Induced Cytotoxicity in Human PC-3 Androgen-Independent Prostate Cancer Cells by Combination With Four Natural Apoptosis-Inducing Anticancer Compounds

Calebin A targets the HIF-1α/NF-κB pathway to suppress colorectal cancer cell migration

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