Anticancer activity of a novel methylated analogue of  L- mimosine against an in vitro model of human malignant melanoma

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The anticancer activity of a series of novel synthesized, hydroxypyridone-based metal chelators (analogues of L-mimosine) was evaluated in an in vitro model of melanoma consisting of malignant melanoma (A375), non-melanoma epidermoid carcinoma (A431) and immortalized non-malignant keratinocyte (HaCaT) cells. More specifically, we have demonstrated that the L-enantiomer of a methylated analogue of L-mimosine (compound 22) can exert a potent anticancer effect in A375 cells when compared to either A431 or HaCaT cells. Moreover, we have demonstrated that this analogue has the ability to i) promote increased generation of reactive oxygen species (ROS), ii) activate both intrinsic and extrinsic apoptosis and iii) induce perturbations in cell cycle growth arrest. Our data highlights the potential of compound 22 to act as a promising therapeutic agent against an in vitro model of human malignant melanoma.

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Elevated copper and oxidative stress in cancer cells as a target for cancer treatment.

Anshul Gupte, Russell Mumper (2009)

As we gain a better understanding of the factors affecting cancer etiology, we can design improved treatment strategies. Over the past three to four decades, there have been numerous successful efforts in recognizing important cellular proteins essential in cancer growth and therefore these proteins have been targeted for cancer treatment. However, studies have shown that targeting one or two proteins in the complex cancer cascade may not be sufficient in controlling and/or inhibiting cancer growth. Therefore, there is a need to examine features which are potentially involved in multiple facets of cancer development. In this review we discuss the targeting of the elevated copper (both in serum and tumor) and oxidative stress levels in cancer with the aid of a copper chelator d-penicillamine (d-pen) for potential cancer treatment. Numerous studies in the literature have reported that both the serum and tumor copper levels are elevated in a variety of malignancies, including both solid tumor and blood cancer. Further, the elevated copper levels have been shown to be directly correlated to cancer progression. Enhanced levels of intrinsic oxidative stress has been shown in variety of tumors, possibly due to the combination of factors such as elevated active metabolism, mitochondrial mutation, cytokines, and inflammation. The cancer cells under sustained ROS stress tend to heavily utilize adaptation mechanisms and may exhaust cellular ROS-buffering capacity. Therefore, the elevated copper levels and increased oxidative stress in cancer cells provide for a prospect of selective cancer treatment.

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Targeting copper in cancer therapy: 'Copper That Cancer'.

Delphine Denoyer, Shashank Masaldan, Sharon La Fontaine … (2015)

Copper is an essential micronutrient involved in fundamental life processes that are conserved throughout all forms of life. The ability of copper to catalyze oxidation-reduction (redox) reactions, which can inadvertently lead to the production of reactive oxygen species (ROS), necessitates the tight homeostatic regulation of copper within the body. Many cancer types exhibit increased intratumoral copper and/or altered systemic copper distribution. The realization that copper serves as a limiting factor for multiple aspects of tumor progression, including growth, angiogenesis and metastasis, has prompted the development of copper-specific chelators as therapies to inhibit these processes. Another therapeutic approach utilizes specific ionophores that deliver copper to cells to increase intracellular copper levels. The therapeutic window between normal and cancerous cells when intracellular copper is forcibly increased, is the premise for the development of copper-ionophores endowed with anticancer properties. Also under investigation is the use of copper to replace platinum in coordination complexes currently used as mainstream chemotherapies. In comparison to platinum-based drugs, these promising copper coordination complexes may be more potent anticancer agents, with reduced toxicity toward normal cells and they may potentially circumvent the chemoresistance associated with recurrent platinum treatment. In addition, cancerous cells can adapt their copper homeostatic mechanisms to acquire resistance to conventional platinum-based drugs and certain copper coordination complexes can re-sensitize cancer cells to these drugs. This review will outline the biological importance of copper and copper homeostasis in mammalian cells, followed by a discussion of our current understanding of copper dysregulation in cancer, and the recent therapeutic advances using copper coordination complexes as anticancer agents.

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L-tyrosine and L-dihydroxyphenylalanine as hormone-like regulators of melanocyte functions.

Andrzej T. Slominski, Michal Zmijewski, John Pawelek (2012)

There is evidence that L-tyrosine and L-dihydroxyphenylalanine (L-DOPA), besides serving as substrates and intermediates of melanogenesis, are also bioregulatory agents acting not only as inducers and positive regulators of melanogenesis but also as regulators of other cellular functions. These can be mediated through action on specific receptors or through non-receptor-mediated mechanisms. The substrate induced (L-tyrosine and/or L-DOPA) melanogenic pathway would autoregulate itself as well as regulate the melanocyte functions through the activity of its structural or regulatory proteins and through intermediates of melanogenesis and melanin itself. Dissection of regulatory and autoregulatory elements of this process may elucidate how substrate-induced autoregulatory pathways have evolved from prokaryotic or simple eukaryotic organisms to complex systems in vertebrates. This could substantiate an older theory proposing that receptors for amino acid-derived hormones arose from the receptors for those amino acids, and that nuclear receptors evolved from primitive intracellular receptors binding nutritional factors or metabolic intermediates. © 2011 John Wiley & Sons A/S.

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Author and article information

Contributors

David Tetard: david.tetard@northumbria.ac.uk

Mihalis I. Panayiotidis:

ORCID: http://orcid.org/0000-0002-1450-3552

m.panagiotidis@northumbria.ac.uk

Journal

Journal ID (nlm-ta): Invest New Drugs

Journal ID (iso-abbrev): Invest New Drugs

Title: Investigational New Drugs

Publisher: Springer US (New York )

ISSN (Print): 0167-6997

ISSN (Electronic): 1573-0646

Publication date (Electronic): 26 June 2019

Publication date PMC-release: 26 June 2019

Publication date (Print): 2020

Volume: 38

Issue: 3

Pages: 621-633

Affiliations

[1 ]GRID grid.42629.3b, ISNI 0000000121965555, Department of Applied Sciences, , Northumbria University, ; Newcastle Upon Tyne, UK

[2 ]GRID grid.12284.3d, ISNI 0000 0001 2170 8022, Department of Molecular Biology & Genetics, , Democritus University of Thrace, ; Alexandroupolis, Greece

Author information

Mihalis I. Panayiotidis http://orcid.org/0000-0002-1450-3552

Article

Publisher ID: 809

DOI: 10.1007/s10637-019-00809-0

PMC ID: 7211211

PubMed ID: 31240512

SO-VID: 1e12dcf5-c935-4420-b115-a324480da2e4

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 3 April 2019

Date accepted : 5 June 2019

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: metal chelators,l-mimosine analogues,skin cancer,anticancer activity,melanoma

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ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: metal chelators, l-mimosine analogues, skin cancer, anticancer activity, melanoma

Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma

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Herbal Medicines Journal (Herb Med J)

Most cited references 68

Elevated copper and oxidative stress in cancer cells as a target for cancer treatment.

Targeting copper in cancer therapy: 'Copper That Cancer'.

L-tyrosine and L-dihydroxyphenylalanine as hormone-like regulators of melanocyte functions.

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