Curcumin and Latest Cancer Therapy

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1		Gerhard Litscher	+ 1737 word(s)	1737	2021-11-07 16:27:43	\|
2	Format Change	Jessie Wu	Meta information modification	1737	2021-11-17 08:59:56	\|

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics13101562

Curcumin incorporated into nanotechnologies has a higher intracellular absorption, a higher targeting rate, increased toxicity to tumor cells, accelerates the activity of caspases and DNA cleavage, decreases the mitochondrial activity of cancer cells, decreases their viability and proliferation, decreases angiogenesis and, finally, it induces apoptosis. It reduces the size of the primary tumor, reverses the resistance to multidrugs in chemotherapy and decreases the resistance to radiation therapy in neoplasms.

Latest curcumin nanoformulations have a huge potential to optimize PDT in cancer therapy, to overcome major side effects, resistance to chemotherapy, relapses and metastases.

cancer curcumin nanomedicine malignancies photodynamic therapy photobiomodulation

1. Curcumin and Latest Cancer Applications

On 14 December 2020, International Agency for Research Cancer (IARC) released Globocan 2020, which published the latest data on the incidence of cancer, which rose to 19.3 million new cases and 10 million cancer deaths in 2020. According to Globocan 2020, which is a statistical database for IARC on incidence and mortality in 185 countries for 36 types of cancers, it has been estimated that cancer had 19.3 million new cases per year, of which breast cancer was in first place, with about 11.7% new cases, followed by lung cancer 11.4%, colorectal 10%, prostate 7.3%, and followed by stomach cancer at 5.6% ^[1]^[2].

The field of cancer research is a dynamic and evolving domain, with a multitude of models and scenarios proposed for examination over the decades on the hidden cause behind tumors development (genetic mutations, microorganisms, metabolic changes and so on), with fluctuating evidence or achievements, whose major goal remains the discovery of new methods and drugs for stopping disease progression and even eradicative therapeutics.

On this line, the cancer stem cell (CSC) model encompasses unusual immortal cells, such as those existing in tumors or blood cancers, similar to regular stem cells, but capable of generating the full range of cells from a given cancer specimen, which, through self-renewal and differentiation into multiple types of cancer cells, are tumorigenic, i.e., they generate recurrences and metastases, and so, supplementary malignancies ^[3]^[4].

In cancers that pursue the CSC model, some intracellular pathways may be attacked with natural compounds, such as curcumin or drugs, to overcome the danger of the development of new tumors at a distance. Promoting appropriate CCS-oriented treatments could improve the survival and quality of the life of patients with metastases ^[5]^[4]^[6]^[7]^[8].

Very recently, research based on this model shows the effectiveness of curcumin in various forms of cancer ^[9].

Even though it has reduced bioavailability, being insoluble in water, curcumin has been intensively studied as an authentic polyphenol and practically the main constituent of Curcuma longa, for its multiple beneficial effects in the treatment of various inflammatory, auto-immune, degenerative diseases, etc., and going to important applications in cancer, not only for the protective effect, but especially by destroying malignant cells. To overcome this drawback, various water-soluble mixtures have been imagined, such as liposomes or the incorporation of curcumin into micelles at the nanometer scale, with raised assimilations appropriate for cancer studies. The first formulations of curcumin in organic solvents proved to be toxic to living cells, and even with genotoxic capabilities. No investigation with curcumin embedded in the micelles has been planned until not long ago. In a recent experiment, Beltzig et al. comparatively investigated the cytotoxic and genotoxic action of genuine curcumin dissolved in ethanol (Cur-E), or integrated into micelles (Cur-M), and evaluated cell killing, apoptosis, necrosis, senolysis and genotoxicity, on a multitude of elementary and settled cell lines, proving that both formulations reduced viability for all cells in the same dose interval. Cur-E and Cur-M induced apoptosis as a function of dose, without senolytic action. Genotoxic repercussions disappeared in the absence of curcumin, denoting a prompt and full repair of DNA. In every experiment, Cur-E and Cur-M were, to the same extent, dynamic, and had important cytotoxic and genotoxic action, starting with 10 μM. Micelles without curcumin content were fully inoperative. The results proved similar in terms of cytotoxicity and genotoxicity for micellar curcumin as the native one, so the administration of micellar curcumin as a dietary supplement is safe and paves the way for new applications ^[10].

Major goals of pharmaceutic investigations are the innovative transport/delivery systems of drugs in cancer treatments. Zarrabi et al. have researched the manufacture of a new intelligent biocompatible stealth-nanoliposome to supply curcumin in cancer therapies. Four distinct classes of liposomes (plus or minus pH-sensitive polymeric film) were obtained by the Mozafari process, and then investigated by multiple trials. The embarkation and deliverance of curcumin were assessed at two different pH values, 7.4 and 6.6, but also the cytotoxicity of the specimens. The optimal average size for the smart stealth-liposome was 40 nm, and the efficacy of the drug’s catch was about 84%, comparatively with 50 nm and only 74% performance by uncovered liposomes. Nano-carrier discharge from the stealth-liposome was better directed than in the uncovered. Experiments have shown the toxicity of drug’s nanocarriers on malignancies. We could conclude that soon, the pH-sensitive intelligent stealth nanoliposome may become a true aspirant in cancer treatments ^[11].

Resistance to medicine and bad outcome in some cancer cases is often due to the hyperactivation of NRF2, a group of transcription factors, i.e., the nuclear factor erythroid 2 p45, detected in some tumors. It was demonstrated that curcumin can induce either cytoprotection or tumor growth by activating NRF2, as a function of the phase of the malignancy. Garufi et al. highlighted the anticancer effects through manifold molecular processes related to curcumin, and recently explored the fundamental molecular sequence of steps linked to making operative NRF2 by the zinc-curcumin [Zn (II) -curc] complex. Indeed, the therapy with Zn (II)–curc raised the NRF2 proteins concentrations and their connections, the heme oxygenase-1 (HO-1) and p62/SQSTM1, while particularly decreased the levels of Keap1 (Kelch-like ECH-associated protein 1), which stopped the NRF2 in all the investigated malignant cell lines. The inhibition of NRF2 or p62/SQSTM1 with distinctive siRNA proved the existence of the communication channel between the two molecules, and that the easily disassemble of any molecule surged the killing of cancer cells by Zn (II)–curc, a fact that could be implemented in the future to improve the receptivity to tumors treatment by this method ^[12].

Curcumin displays multiple proven effects on cells; for example, an inhibitive action on thrombocytes, but not known if it is owed to thrombocyte apoptosis or to pro-coagulant platelet organization.

Recently, Rukoyatkina et al. reported that curcumin did not initiate caspase 3—relying on the apoptosis of human thrombocytes, but led to the organization of pro-coagulant thrombocytes. At 5 µM concentration, the effect increased, but at ten times’ higher concentration, the thrombocytes apoptosis was stopped by the suppression of ABT-737 (small molecule drug that inhibits Bcl-2 and Bcl-xL) that was interfered with thrombin production.

Curcumin did not alter thrombocytes’ ability to survive at low concentrations but decreased it by 17% at higher concentrations. Autophagy caused by curcumin in human thrombocytes was accompanied by the operative configuration of adenosine monophosphate kinase (AMP), and the cessation of protein kinase B function. Curcumin could block the P-glycoprotein (P-gp) in tumors, and therefore defeat the manifold medicines resistance, and likewise could also stop the thrombocytes P-gp action. The effects of curcumin on human thrombocytes are due to complex processes through pro-coagulant thrombocytes organization, and so it can support pro—or against caspase—subordinate thrombocyte’s death, but only in distinctive cases ^[13].

Systematically checking the abnormal functioning of cells, tissues or organs in the inceptive steps of the initiation of malignant processes and the monitorization of the cellular oxygenation is of maximum significance, both for the fundamental applications, but also in the practical medical ones.

A non-invasive modality for both the in vivo and in vitro assessment of cellular oxygenation is evaluating the lifespan of the luminescence of molecular sensors, but still very difficult in the case of increased oxidative stress.

Molecular probes, such as mitochondrial probes or [Ru (Phen)3]²⁺ state-of-the-art, intact cell phosphorescence imaging technologies applied by Huntosova et al., in a model of chorioallantoic membrane (CAM), offer reduced phototoxicities and could also be applied in curcumin cancer therapy in tumors originating from the neuroglia of the brain or spinal cord. These results could be useful and universalized for the evaluation of tissue oxygenation as an advanced and original method, based on the analogies between diverse interacting biological factors, especially in cancer therapies that deal with metabolic or oxygen changes, glucose and lipid loss, and so on ^[14].

Important attempts to improve the potency of targeted drug carriers in the lung cancer were made, but the prognosis is still very poor, with only 15% survivors, 5 years after identification. The best choice for the direct administration of chemotherapy to the lungs would be the inhalation formulation.

Currently, this type of formulation to accomplish successfully, at the same time, a significant dose of specific chemicals that are selectively destructive to malignant cells and tissues in the solid tumor and to function with reduced local lung toxicity, is still an aim, as only 10–30% of lung chemotherapy nowadays already has the quality of being toxic ^[15].

Lee et al. imagined a dry powder easy to inhale (DPI) holding a chemotherapeutic agent (paclitaxel, PTX) and the native antioxidant curcumin (CUR) that defends the healthy cells to be damaged during direct lung transfer chemotherapy. Grinding CUR and PTX in co-jet as aerosol formulation, with more than 60% of very fine particles and a fit mass median aerodynamic diameter, exhibits an important cytotoxic effect for lung tumors, giving rise to apoptosis/necrotic cell killing, extending mitochondrial oxidative stress (ROS), depolarizing the mitochondria membranes, and decreasing the ATP in malignant cells. Incorporating CUR is decisive for correcting the cytotoxic effects of PTX against healthy cells and depends on dose, providing an easy and efficient DPI formulation with special discriminating cytotoxicity in lung malignancies ^[15].

In another experiment concerning lung cancer, Wan Mohd Tajuddin et al. studied the diarylpentanoid (DAP), changed the structure analog from the genuine curcumin, and proved to improve anticancer effects in different forms of malignancies, by comparing the outcomes (toxic impact, proliferative and apoptotic action) on two subtypes of non-small cell lung cancer (NSCLC) cells: the squamous cell carcinoma (NCI-H520) and the adenocarcinoma (NCI-H23). The gene expression to reveal the main signaling pathways, the targeted genes, the cytotoxicity screening, the anti-proliferative action, as well as the apoptosis linked to the rise in caspase-3 activity and decrease in Bcl-2 protein concentration were investigated and proved to be function of dose and time in all studied cells. This new compound, derived from curcumin, should be henceforth investigated as a possible representative anticancer drug for NSCLC cancer treatment ^[16].

References

Globocan 2020: New Global Cancer Data. 17 December 2020. Available online: https://www.uicc.org/news/globocan-2020-new-global-cancer-data (accessed on 20 July 2021).
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Reddy, R.M.; Kakarala, M.; Wicha, M.S. Clinical Trial Design for Testing the Stem Cell Model for the Prevention and Treatment of Cancer. Cancers 2011, 3, 2696–2708.
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Kakarala, M.; Brenner, D.E.; Korkaya, H.; Cheng, C.; Tazi, K.; Ginestier, C.; Liu, S.; Dontu, G.; Wicha, M.S. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res. Treat. 2010, 122, 77–785.
Carroll, R.E.; Benya, R.V.; Turgeon, D.K.; Vareed, S.; Neuman, M.; Rodriguez, L.; Kakarala, M.; Carpenter, P.M.; McLaren, C.; Meyskens, F.L., Jr.; et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev. Res. 2011, 4, 354–364.
Mao, X.; Zhang, X.; Zheng, X.; Chen, Y.; Xuan, Z.; Huang, P. Curcumin suppresses LGR5(+) colorectal cancer stem cells by inducing autophagy and via repressing TFAP2A-mediated ECM pathway. J. Nat. Med. 2021, 75, 590–601.
Beltzig, L.; Frumkina, A.; Schwarzenbach, C.; Kaina, B. Cytotoxic, Genotoxic and Senolytic Potential of Native and Micellar Curcumin. Nutrients 2021, 13, 2385.
Zarrabi, A.; Zarepour, A.; Khosravi, A.; Alimohammadi, Z.; Thakur, V.K. Synthesis of Curcumin Loaded Smart pH-Responsive Stealth Liposome as a Novel Nanocarrier for Cancer Treatment. Fibers 2021, 9, 19.
Garufi, A.; Giorno, E.; Gilardini Montani, M.S.; Pistritto, G.; Crispini, A.; Cirone, M.; D’Orazi, G. p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex. Biomolecules 2021, 11, 348.
Rukoyatkina, N.; Shpakova, V.; Sudnitsyna, J.; Panteleev, M.; Makhoul, S.; Gambaryan, S.; Jurk, K. Curcumin at Low Doses Potentiates and at High Doses Inhibits ABT-737-Induced Platelet Apoptosis. Int. J. Mol. Sci. 2021, 22, 5405.
Huntosova, V.; Horvath, D.; Seliga, R.; Wagnieres, G. Influence of Oxidative Stress on Time-Resolved Oxygen Detection by 2+ In Vivo and In Vitro. Molecules 2021, 26, 485.
Lee, W.-H.; Loo, C.-Y.; Traini, D.; Young, P.M. Development and Evaluation of Paclitaxel and Curcumin Dry Powder for Inhalation Lung Cancer Treatment. Pharmaceutics 2021, 13, 9.
Wan Mohd Tajuddin, W.N.B.; Abas, F.; Othman, I.; Naidu, R. Molecular Mechanisms of Antiproliferative and Apoptosis Activity by 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)1,4-Pentadiene-3-one (MS13) on Human Non-Small Cell Lung Cancer Cells. Int. J. Mol. Sci. 2021, 22, 7424.

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Gerhard Litscher

Laura-Marinela AILIOAIE

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1. Curcumin and Latest Cancer Applications

References