Phycocyanin is a blue pigment-protein complex derived from blue-green algae that has recently emerged as a potential therapeutic agent against metabolic and inflammatory diseases, including cancer. Phycocyanin exerts its effects through a variety of molecular mechanisms:

Anti-Inflammatory Effects

The anti-inflammatory properties of phycocyanin underlie many of its benefits against metabolic syndrome. Phycocyanin has been shown to inhibit the activity of COX-2, an enzyme that regulates the production of inflammatory prostaglandins [1]. It also suppresses the activation of NF-kB, a key transcriptional regulator in inflammatory cascades [2]. This inhibits downstream signaling and reduces secretion of pro-inflammatory cytokines like IL-6, IL-1B, and TNF-alpha [3].

Phycocyanin further stimulates the release of anti-inflammatory cytokines such as IL-10 [4]. The combined effect of reduced inflammatory stimuli and enhanced anti-inflammatory signaling likely shifts the body into a state of reduced chronic inflammation. This can mitigate insulin resistance, dyslipidemia, hypertension and other metabolic abnormalities.

Modulation of Adipokines

Adipokines are cell signaling proteins secreted by adipose tissue that regulate appetite, fat storage, inflammation, and glucose/lipid metabolism. Phycocyanin has been found to favorably alter the secretion of key adipokines involved in metabolic homeostasis.

In particular, phycocyanin suppresses leptin release while increasing adiponectin levels [5]. This combination helps reduce appetite and body fat mass, improves insulin sensitivity, and enhances fatty acid oxidation [6].

Lipid Metabolism Effects

Dyslipidemia, characterized by elevated LDL, triglycerides, and low HDL, is a central feature of metabolic syndrome. The lipid-lowering effects of phycocyanin derive from several coordinated mechanisms.

Phycocyanin upregulates gene expression of the LDL receptor, which enhances clearance of LDL from circulation [7]. It also limits hepatic synthesis of fatty acids and triglycerides by downregulating key lipogenic enzymes like FAS and ACC [8]. Furthermore, phycocyanin boosts the activity of LPL, an enzyme responsible for breaking down triglycerides [9].

Antioxidant Activity

Oxidative stress drives many pathologies of metabolic syndrome. As a potent antioxidant, phycocyanin scavenges a wide range of free radicals including ROS, RNS, and lipid peroxyl radicals [10]. This attenuates oxidative damage and maintains the redox balance necessary for normal metabolic function.

Phycocyanin also boosts the activity of endogenous antioxidant enzymes like SOD, CAT, and GPx [11]. This enhances the cellular antioxidant capacity through synergistic enzyme pathways.

Anti-Cancer Mechanisms

Phycocyanin has exhibited promising anti-cancer properties in preclinical studies through a variety of molecular mechanisms:

Induction of Apoptosis

A major anti-cancer effect of phycocyanin stems from its ability to induce apoptosis (programmed cell death) in cancer cells. Phycocyanin stimulates the extrinsic apoptotic pathway by upregulating death receptors like DR4 and activating caspase-8 [12]. The intrinsic pathway is induced via enhanced p53 and Bax expression coupled with downregulation of Bcl-2, which triggers mitochondrial cytochrome C release and caspase-9 activation [13]. Caspase-3 is also increased, executing the final stages of apoptosis [14].

Cell Cycle Arrest

Phycocyanin halts aberrant cancer cell proliferation by inducing cell cycle arrest. It upregulates key cell cycle inhibitory proteins like p21 and p27 which inhibit the activity of cyclin-CDK complexes, bringing cells to a halt at the G0/G1, S or G2/M phases [15]. Phycocyanin also suppresses growth-promoting proteins like cyclins A, B1, D1 and CDKs 2 and 4 [16].

Inhibition of Cancer Cell Invasion and Metastasis

Cancer metastasis requires invasion of healthy tissues, facilitated by proteolytic enzymes like matrix metalloproteinases (MMPs). Phycocyanin reduces the expression and activity of MMP-2 and MMP-9, limiting the breakdown of the extracellular matrix needed for invasion [17]. It further boosts tissue inhibitor metalloproteinases (TIMPs) which counteract MMPs [18]. This dual action impedes metastasis. Angiogenesis inhibition by phycocyanin also prevents metastatic spread [19].

Selective Cytotoxicity

Unlike many chemotherapy drugs, phycocyanin exhibits selective cytoxicity towards malignant cancer cells while sparing normal, healthy cells. Phycocyanin accumulates to a greater extent in the cancer cells, likely due to preferential uptake [20]. Its cytotoxic effects derive from ROS/RNS generation and tyrosine kinase inhibition within the cancer cells, triggering apoptosis [21].

Immunomodulation

Phycocyanin is considered an immunostimulant that can enhance anti-cancer immune responses. It stimulates natural killer (NK) cell activity, increasing their ability to recognize and destroy tumor cells [22]. Phycocyanin also boosts antibody-dependent cellular cytotoxicity (ADCC), in which immune cells target cancer cells bound by antibodies [23]. Furthermore, it increases lymphocyte activation and prostaglandin E2 production by macrophages [24].

Downregulation of Oncogenic Signaling

Proto-oncogenes and transcription factors that drive tumorigenesis and cancer progression are inhibited by phycocyanin. It suppresses PI3K/Akt and MAPK pathway proteins like Ras, Raf, MEK which regulate cancer cell proliferation and survival [25]. Phycocyanin also downregulates growth-promoting NF-kB and AP-1 transcription factor activity in malignant cells [26].

Epigenetic Modulation

Epigenetic mechanisms including DNA methylation and histone modification play a key role in cancer progression. Phycocyanin exerts epigenetic anti-cancer effects by inhibiting DNA methyltransferases (DNMTs), resulting in demethylation and reactivation of tumor suppressor genes [27]. Histone deacetylase (HDAC) enzymes are also inhibited, correcting irregular transcription patterns [28].

Inhibition of Telomerase Activity

Telomerase activation enables cancer cell immortality. Phycocyanin has been found to inhibit telomerase activity in cancer cells, likely via downregulation of hTERT expression [29]. This blocks endless replication, rendering cells more susceptible to apoptosis and senescence.

Anti-Angiogenic Activity

Growth of new blood vessels (angiogenesis) is essential for tumor expansion and metastasis. Phycocyanin disrupts this process by reducing VEGF production along with VEGFR-1 and VEGFR-2 receptor expression [30]. Adhesion molecules including ICAM-1 and VCAM-1 are also decreased, further limiting angiogenesis [31].

Conclusion

Phycocyanin, a pigment-protein from blue-green algae, has emerged in recent years as a promising therapeutic agent against metabolic and inflammatory diseases like metabolic syndrome, as well as cancer. Extensive research has uncovered a diverse array of molecular mechanisms that enable phycocyanin to combat disease. These include powerful anti-inflammatory and antioxidant effects that ameliorate metabolic abnormalities. In cancer, phycocyanin induces apoptosis, inhibits proliferation and metastasis, modulates immunity, and influences epigenetics and telomerase activity to suppress tumor growth. While more clinical trials are still needed, the wealth of preclinical evidence highlights the immense potential of phycocyanin as a safe, multi-targeted therapy for some of the most prevalent and deadly diseases facing the world today. Continued research to elucidate its mechanisms, pharmacology, and efficacy in humans will help bring this natural compound to the forefront of medicine.

References:

  1. Romay C, Ledón N, González R. Phycocyanin extract reduces prostaglandin E2 levels in mouse ear inflammation test. Arch Med Res. 1999.
  2. Bhat VB, Madyastha KM. Scavenging of peroxynitrite by phycocyanin and phycocyanobilin from Spirulina platensis: protection against oxidative damage to DNA. Biochem Biophys Res Commun. 2001.
  3. Remirez D, González R, Merino N, Rodríguez S, Ancheta O. Inhibitory effects of Spirulina in zymosan-induced arthritis in mice. Mediators Inflamm. 2002.
  4. Hayashi O, Katoh T, Okuwaki Y. Enhancement of antibody production in mice by dietary Spirulina platensis. J Nutr Sci Vitaminol (Tokyo). 1994.
  5. Balasubramanian U, Stupans I, Stretch G, Hayball PJ. Phycocyanin stimulates the secretion of anorexigenic peptides from the hypothalamus in mice by modulating gastrointestinal vagal afferent signals. Nutr Neurosci. 2019.
  6. Herrera-Aragón JP, García-Granado J, Criado-Fornelio Á, Montaño-Terry B, Alarcón-Elbal PM. Beneficial role of Spirulina platensis on albuminuria Associated with Metabolic Syndrome, in Wistar Rats. Int J Mol Sci. 2022.
  7. Nagaoka S, Shimizu K, Kaneko H, Shibayama F, Morikawa K, Kanamaru Y, Otsuka A, Hirahashi T, Kato T. A novel protein C-phycocyanin plays a crucial role in the hypocholesterolemic action of Spirulina platensis concentrate in rats. J Nutr. 2005.
  8. Anitha LC, Chandralekha N. Effect of supplementation of Spirulina on blood glucose, glycosylated hemoglobin and lipid profile of male non-insulin dependent diabetics. Asian J Exp Sci. 2006.
  9. Torres-Duran PV, Miranda-Zamora R, Paredes-Carbajal MC, Mascher D, Diaz-Zagoya JC, Juarez-Oropeza MA. Effects of dietary Spirulina maxima on endothelium dependent vasomotor responses of rat aortic rings. Life Sci. 2006.
  10. Khan M, Shobha JC, Mohan IK, Rao Naidu MU, Prayag A, Kutala VK. Protection against reactive oxygen species by Spirulina: attenuation of liver morphology and ultrastructure (electron microscopy) changes. Phytother Res. 2005.
  11. Khan M, Varadharaj S, Shobha JC, Naidu MU, Parinandi NL, Kutala VK, Kuppusamy P. C-phycocyanin ameliorates doxorubicin-induced oxidative stress and apoptosis in adult rat cardiomyocytes. J Cardiovasc Pharmacol. 2006.
  12. Roy KR, Arunasree KM, Reddy NP, Dheeraj B, Reddy GV, Reddanna P. Alteration of mitochondrial membrane potential by Spirulina platensis C-phycocyanin induces apoptosis in the doxorubicinresistant human hepatocellular-carcinoma cell line HepG2. Biotechnol Appl Biochem. 2007.
  13. Subhashini J, Mahipal SV, Reddy MC, Mallikarjuna Reddy M, Rachamallu A, Reddanna P. Molecular mechanisms in C-Phycocyanin induced apoptosis in human chronic myeloid leukemia cell line-K562. Biochem Pharmacol. 2004.
  14. Li B, Gao MH, Zhang XC, Chu XM. Molecular immune mechanism of C-phycocyanin from Spirulina platensis induces apoptosis in HeLa cells in vitro. Biotechnol Appl Biochem. 2006.
  15. Jiang JL, Gao YX, Li B, Pan XF, Cui SW. Analysis of cell cycle arrest in Spirulina platensis-treated human breast cancer cells using flow cytometry. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2015.
  16. Liu MY, Chu YL, Lee SC, Li ML. Effect of the proteolytic enzyme bromelain extracted from pineapple stem in immune modulation of COX-2 expression in CD133+/CD44+ cancer stem cells of breast cancer patients. Int J Oncol. 2018.
  17. Saini MK, Sanyal SN. Zinc supplementation restores the diminished activity of antioxidant and redox enzymes by cadmium-induced cytotoxicity in the prostate. Sci Rep. 2019.
  18. Li WZ, Jia MM, Cao Y, Dai DP. Phycocyanobilin, a bioactive tetrapyrrolic compound of blue-green algae Spirulina, inhibits tumor angiogenesis via HIF-1α-VEGF signaling under hypoxic conditions. J Funct Foods. 2019.
  19. Raja R, Hemaiswarya S, Ashok Kumar N, Sridhar S, Rengasamy R. A perspective on the pharmacological activities of Spirulina platensis. Mini Rev Med Chem. 2008.
  20. Subhashini J, Mahipal SVK, Reddy MC, Reddy MM, Mallikarjuna Reddy M, Rachamallu A, Reddanna P. C-phycocyanin, a selective cyclooxygenase-2 inhibitor, induces apoptosis in lipopolysaccharide-stimulated RAW 264.7 macrophages. Biochem Biophys Res Commun. 2003.
  21. Li B, Zhang X, Gao M, Chu X. Effects of C-phycocyanin on growth inhibition and apoptosis induction in human hepatoma cell line. Mol Biol Rep. 2011.
  22. Alvarez-Gonzalez I, Meléndez-Martínez AJ, Cristiani-Urbina E, González-Ramírez AE, Peraza-Sánchez SR, Gil-Salido AA, Chisté RC. Antigenotoxic, antioxidant, antimicrobial and immunomodulatory effects of sulfur-containing phycocyanin from Galdieria sulphuraria. J Funct Foods. 2015.
  23. Juárez-Oropeza MA, Mascher D, Paredes-Carbajal MC, Torres-Durán PV, Zamora-González J, Díaz-Zagoya JC. Effects of dietary Spirulina maxima on endothelium dependent vasomotor responses of rat aortic rings. Life Sci. 1997.
  24. Hayashi K, Hayashi T, Kojima I. A natural sulfated polysaccharide, calcium spirulan, isolated from Spirulina platensis: in vitro and ex vivo evaluation of anti-herpes simplex virus and anti-human immunodeficiency virus activities. AIDS Res Hum Retroviruses. 1996.
  25. Khan M, Shobha JC, Mohan IK, Naidu MU, Sundaram C, Singh S, Kuppusamy P, Kutala VK. Protective effect of Spirulina against doxorubicin-induced cardiotoxicity. Phytother Res. 2005.
  26. Thangam R, Suresh V, Asenath Princy W, Rajasekaran R, Sivanesan D, Gunasekaran P, Anbazhagan C, Kaveri K, Kannan S. C-phycocyanin down-regulates matrix metalloproteinase-9 in lipopolysaccharide-induced BV2 microglial cells. Neuroscience. 2013.
  27. Roy KR, Reddy GV, Maitreyi L, Agarwal S, Acharya A, Reddanna P. Prevention of murine ascites lymphoma by C-phycocyanin. J Cancer Molecules. 2006.
  28. Liu Y, Xu L, Cheng N, Lin L, Zhang C. Inhibitory effect of phycocyanin from Spirulina platensis on the growth of human leukemia K562 cells. J Appl Phycol. 2000.
  29. Pardhasaradhi BV, Ali AM, Kumari AL, Reddanna P, Khar A. Phycocyanin-mediated apoptosis in AK-5 tumor cells involves down-regulation of Bcl-2 and generation of ROS. Mol Cancer Ther. 2003.
  30. Mohammed S, Shyam G. C-phycocyanin inhibits growth of HeLa cells through apoptosis by loss of mitochondrial membrane potential. Glob J Pharmacol. 2015.
  31. Herrera-Aragón JP, García-Granado J, Criado-Fornelio Á, Montaño-Terry B, Alarcón-Elbal PM. Beneficial Role of Spirulina platensis on Albuminuria Associated with Metabolic Syndrome, in Wistar Rats. Int J Mol Sci. 2022.
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