Anticancer Activity of Two Novel Hydroxylated Biphenyl Compounds toward Malignant Melanoma Cells

Pisano, Marina; Dettori, Maria Antonietta; Fabbri, D.; Delogu, Giovanna; Palmieri, Giuseppe; Rozzo, Carla

doi:10.3390/ijms22115636

Cited by 13 publications

(6 citation statements)

References 41 publications

(88 reference statements)

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“…Therefore, we analyzed some molecular markers of programmed cell death. The cleaved form of poly (ADP-ribose) polymerase 1 (cleaved-PARP1) is obtained through the activity of caspase 3 or caspase 7 in cells undergoing apoptosis [ 47 , 48 ]. After 24 h of HPF treatment, in all melanoma cell lines, immunoblots showed a decrease of bands representing full-length PARP1 expression and a correspondent increase of higher mobility band displaying cleaved-PARP1 level ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

Cardile

Zanrè

Campagnari

et al. 2023

IJMS

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Hyperforin (HPF), the main component responsible for the antidepressant action of Hypericum perforatum, displays additional beneficial properties including anti-inflammatory, antimicrobic, and antitumor activities. Among its antitumor effects, HPF activity on melanoma is poorly documented. Melanoma, especially BRAF-mutated melanoma, is still a high-mortality tumor type and the currently available therapies do not provide solutions. We investigated HPF’s antimelanoma effectiveness in A375, FO1 and SK-Mel-28 human BRAF-mutated cell lines. Cell viability assays documented that all melanoma cells were affected by low HPF concentrations (EC50% 2–4 µM) in a time-dependent manner. A Br-deoxy-uridine incorporation assay attested a significant reduction of cell proliferation accompanied by decreased expression of cyclin D1 and A2, CDK4 and of the Rb protein phosphorylation, as assessed by immunoblots. In addition, the expression of P21/waf1 and the activated form of P53 were increased in A375 and SK-Mel-28 cells. Furthermore, HPF exerts cytotoxic effects. Apoptosis is induced 24 h after HPF administration, documented by an increase of cleaved-PARP1 and a decrease of both Bcl2 and Bcl-xL expression levels. Autophagy is induced, attested by an augmented LC3B expression and augmentation of the activated form of AMPK. Moreover, HPF lowers GPX4 enzyme expression, suggesting ferroptosis induction. HPF has been reported to activate the TRPC6 Ca++ channel and/or Ca++ and Zn++ release from mitochondria stores, increasing cytosolic Ca++ and Zn++ concentrations. Our data highlighted that HPF affects many cell-signaling pathways, including signaling induced by Ca++, such as FRA1, pcJun and pCREB, the expression or activity of which are increased shortly after treatment. However, the blockage of the TRPC6 Ca++ channel or the use of Ca++ and Zn++ chelators do not hinder HPF cytostatic/cytotoxic activity, suggesting that damages induced in melanoma cells may pass through other pathways. Remarkably, 24 h after HPF treatment, the expression of activated forms of the transcription factors NF-κB P65 subunit and STAT3 are significantly lowered. Several cytosolic (PGM2, LDHA and pPKM2) and mitochondrial (UQCRC1, COX4 and ATP5B) enzymes are downregulated by HPF treatment, suggesting a generalized reduction of vital functions in melanoma cells. In line with these results is the recognized ability of HPF to affect mitochondrial membrane potential by acting as a protonophore. Finally, HPF can hinder both melanoma cell migration and colony formation in soft agar. In conclusion, we provide evidence of the pleiotropic antitumor effects induced by HPF in melanoma cells.

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Section: Resultsmentioning

confidence: 99%

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

Cardile

Zanrè

Campagnari

et al. 2023

IJMS

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“…Other potential targets revealed during the in silico “target fishing” reverse screening, including Poly(ADP-ribose)polymerase (PARP), 82, 83 phosphodiesterase type 5, 84, 85 orphan nuclear receptor LRH-1, 86, 87 nuclear receptor ROR-gamma, 88, 89 matrix metallopeptidase 9 (MMP9), 90 NAD-dependent deacetylase Sirtuin 2, 91 and cholesterol ester transfer protein, 92 all believed to play important roles in skin carcinogenesis. There is no doubt that the wealth of information gathered here will be useful in further studies towards the optimizing the hit molecules’ activity and determining their putative drug target and potential mechanism(s) of action.…”

Section: Resultsmentioning

confidence: 99%

“…78 It should also be mentioned that PI3K/RAC alpha serine/threonine protein kinase (AKT)/mTOR signaling pathway has been shown to be over-activated in some types of skin cancers, 80 with the anti-proliferative activity of some phenolic compounds against SK-MEL-2 cancer cells attributed to the downregulation of the PI3K/AKT/mTOR signaling pathway, which induces a mitochondrial-dependent apoptosis. 81 Other potential targets revealed during the in silico "target fishing" reverse screening, including Poly(ADPribose)polymerase (PARP), 82,83 phosphodiesterase type 5, 84,85 orphan nuclear receptor LRH-1, 86,87 nuclear receptor ROR-gamma, 88,89 matrix metallopeptidase 9 (MMP9), 90 NAD-dependent deacetylase Sirtuin 2, 91 and cholesterol ester transfer protein, 92 all believed to play important roles in skin carcinogenesis. There is no doubt that the wealth of information gathered here will be useful in further studies towards the optimizing the hit molecules' activity and determining their putative drug target and potential mechanism(s) of action.…”

Section: In Silico Target(s) Prediction Pharmacokinetic and Admet Stu...mentioning

confidence: 99%

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

Boateng

Roy

Agbo

et al. 2022

Preprint

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Melanoma and nonmelanoma skin cancer are the most lethal and commonest forms of skin cancers affecting one fifth of the US population. With the aim of identifying new lead compounds as starting point for attaining cost effective therapies, a small library of about 90 molecules was screened in vitro against A375, SKMEL28, A431, SCC12 skin cancer cell lines. About 35 of them, mainly dihydroquinolines, CC and CN linked biphenyls, and substituted methyl gallate or aniline derivatives, displayed low micromolar range activities, primarily against the A431 and SCC12 squamous carcinoma cell lines, with only a handful of these compounds displaying any activity against the A375 and SKMEL28 melanoma cell lines. Compounds 11 (A431: IC50 = 5.0 lower case Greek muM, SCC12: IC50 = 2.9 lower case Greek muM, SKMEL-28: IC50 = 4.9 lower case Greek muM, A375: IC50 = 6.7 lower case Greek muM) and 13 (A431: IC50 = 5.0 lower case Greek muM, SCC-12: IC50 = 3.3 lower case Greek muM, SKMEL-28: IC50 = 13.8 lower case Greek muM, A375: IC50 = 17.1 lower case Greek muM) were the most active across all these cell lines. Furthermore, many of the hit compounds showed little to no activity against mammalian nontumorigenic immortalized HaCaT cells, with a far better selectivity index than cisplatin (a well-known anticancer agent used as a positive control). Compounds 11 and 13 significantly and dose dependently induced apoptosis of SCC12 and SKMEL28 cells as evidenced by the downregulation of Bcl2 and upregulation of Bax protein expression levels, and by cleaved caspase 3, caspase 9 and PARP levels. Both agents also significantly reduced scratch wound healing, colony formation, and activated expression levels of major cancer molecular targets such as RSK/AKT/ERK1/2 and S6K1. To provide a better attribute profile for each of the hit molecules, in silico target(s) prediction, pharmacokinetic and ADMET studies are also reported, together with some preliminary structure activity relationship outlines. The SwissTargetPrediction web-based tool identified CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, as likely targets for these hit compounds. Furthermore, the SwissADME web_tool predicted these compounds to exhibit high GI tract absorption, good skin permeation, and a viable biodegradability profile. To summarize, these data highlight the promising anticancer potential of these small molecules leads, warranting further investigation and/or optimization towards obtaining clinical candidates for combatting both melanoma and nonmelanoma skin cancers.

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“…It serves as a central building block for basic liquid crystal and fluorescent layers in OLEDs [3,4]. The ability of biphenyls to undergo chemical changes to form substituted biphenyls has many biological and pharmaceutical applications, including anti-inflammatory, antimicrobial, antifungal, antidiabetic, anti-tumor, and anticancer properties [5][6][7][8][9]. The search for new and efficient pharmaceuticals is a constant struggle for medicinal chemists, in view of the fact that the new compounds synthesized by various standard methods should be safe, effective, and have fewer side effects.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, crystal structure, DFT/HF, Hirshfeld surface, and molecular docking analysis of 4-(tert-butyl)-4-nitro-1,1-biphenyl

et al. 2023

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4-(tert-Butyl)-4-nitro-1,1-biphenyl has been synthesized, and its structure has been characterized by using some spectroscopic and single-crystal X-ray diffraction techniques. It crystallizes in a monoclinic crystal system with space group P21/n and unit cell parameters: a = 6.4478(3) Å, b = 9.2477(4) Å, c = 23.4572(9) Å, β = 95.114(4)°, V = 1393.11(10) Å3, Z = 4. The molecular structure has been solved by using the intrinsic phasing method. The crystal structure is stabilized by C-H···O interactions. Computational studies were performed using density functional theory (DFT) and Hartree-Fock (HF) methods. The optimized geometry obtained from DFT and HF in the gas phase was compared with solid-phase experimental data retrieved from single-crystal X-ray diffraction results. Frontier molecular orbitals, such as the HOMO/LUMO energy gap, the molecular electrostatic potential, and Mulliken atomic charges, have been investigated. The HOMO LUMO energy gap of 3.97 eV indicates that the molecule is soft and highly reactive. The Hirshfeld surface analysis and their associated fingerprint plots have been used to quantitatively validate the interactions. Further insilico molecular docking studies have been performed with the molecular target Type-II topoisomerase (PDB ID: 1JIJ) and their results suggest that 4-(tert-butyl)-4-nitro-1,1-biphenyl could be considered an anticancer drug.

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Anticancer Activity of Two Novel Hydroxylated Biphenyl Compounds toward Malignant Melanoma Cells

Cited by 13 publications

References 41 publications

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

Synthesis, crystal structure, DFT/HF, Hirshfeld surface, and molecular docking analysis of 4-(tert-butyl)-4-nitro-1,1-biphenyl

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