Marine Cyanobacterial Peptides in Neuroblastoma: Comparison
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Please note this is a comparison between Version 1 by Salman Ahmed and Version 3 by Lindsay Dong.

Neuroblastoma is the most prevalent extracranial solid tumor in pediatric patients, originating from sympathetic nervous system cells. Metastasis can be observed in approximately 70% of individuals after diagnosis, and the prognosis is poor. The current care methods used, which include surgical removal as well as radio and chemotherapy, are largely unsuccessful, with high mortality and relapse rates. Marine cyanobacteria are a key source of physiologically active metabolites, which have recently received attention owing to their anticancer potential. Marine peptides possess several advantages over proteins or antibodies, including small size, simple manufacturing, cell membrane crossing capabilities, minimal drug–drug interactions, minimal changes in blood–brain barrier (BBB) integrity, selective targeting, chemical and biological diversities, and effects on liver and kidney functions.

  • marine cyanopeptides
  • apoptosis
  • autophagy
  • cell cycle arrest
  • antimetastatic

1. Introduction

The most common type of extracranial solid tumor in pediatric patients is neuroblastoma (NB), which is derived from the cells of the sympathetic nervous system. It is most common in the abdomen area, particularly around the adrenal glands, but can also appear in nerve tissues of the neck, chest, abdomen or pelvis. Neuroblastoma is diagnosed in children under two with a poor prognosis. In almost 70% of patients, metastasis can be seen after diagnosis. Conventional treatments for NB include chemotherapy (e.g., Cyclophosphamide or Dinutuximab), radiotherapy, immunotherapy (e.g., CAR T cell- chimeric antigen receptor T cell), and surgical tumor resection. Dinutuximab is a chimeric antibody directed against GD2 present on neuroblastoma cells and used as an immunotherapeutic agent in selected neuroblastoma patients. Despite the wide range of cancer therapies, current therapies do not provide optimal results since cancer recurrence and metastasis are prevalent. NB thus remains a significant problem with a high mortality rate [1][2][1,2].
Cancer chemotherapy is undergoing a dramatic transformation as a growing number of targeted drugs increase the therapeutic efficacy, minimize destructive impacts, and improve health outcomes. Despite recent advances in chemotherapy, the prognosis of advanced NB remains poor, and its treatment is associated with adverse side effects (toxicity and myelosuppression). Surgical procedures are invasive and may result in inadequate tumor excision, requiring additional chemo- and radiation therapies and stem cell transplantation. Therefore, it is crucial to discover more selective chemicals for cancer treatment with fewer adverse effects, more robust therapeutic efficacy, and a reduced resistance index. Increased progress is underway to obtain effective naturally sourced chemicals. Accordingly, new anticancer medicines with minimal adverse effects are needed for the effective treatment of NB [3][4][5][3,4,5].
Natural compounds, mainly from marine organisms (microbes and plants), have been widely studied as complementary and supportive therapies for cancers aimed at affording a preventative role in cancer care, reducing the adverse effects of oncologic treatments, and overcoming cancer drug resistance [6][7][8][6,7,8].
Marine medicines constitute an essential source of anticancer treatments. Despite the vast potential of new marine drugs, only a few pharmaceuticals have been used for cancer treatment to date. Following the initial acceptance of cytarabine in 1969, the FDA approved several marine-derived compounds as anticancer drugs. The discovery of ulithiacyclamide, the first maritime antitumor peptide, was followed by other marine anticancer peptides, such as didemnin B, dolastatin 10, kahalalide F, hemiasterlin, cemadotin, soblidotin, aplidine, and others, with subsequent clinical trials [9][10][11][12][9,10,11,12]. Marine cyanobacteria have aroused considerable interest in marine ecology due to their abundance and ability to provide novel chemotypes with substantial biological activity.

2. Marine Cyanobacterial Peptides

Cyanobacteria, which are among the oldest aquatic and photosynthetic oxygenic prokaryotes, are found worldwide. The presence of numerous bioactive secondary metabolites in cyanobacteria from various habitats, especially marine cyanobacteria, has recently been discovered. Bioactive compounds from aquatic cyanobacteria help them better adapt to a variety of complex, hypersaline, high-pressure, barren marine habitats by acting as chemical defenses. These cyanobacterial secondary metabolites exhibit a wide range of biological activities, including anti-tumor, antibacterial, enzyme inhibition, parasite resistance, anti-inflammatory, and other biological activities, in addition to having a significant impact on the growth and reproduction of cyanobacteria [13][63]. As a result, they received interest from scholars in various experimental fields, including medicinal chemistry, pharmacology, and marine chemical ecology [14][64]. Over 400 new natural compounds from marine cyanobacteria have been identified over the past decade thanks to the International Cooperative Biodiversity Group (ICGB) program [15][65]. Peptides and compounds containing peptides are the main secondary metabolites among these substances [16][66]. A total of 126 novel peptide compounds, mostly from the genera Lyngbya, Oscillatoria, and Symploca, were extracted from marine cyanobacteria by the end of 2016. Nevertheless, two new genera, Moorea and Okeania, previously recognized as the polyphyletic cyanobacterial genus Lyngbya, were identified by genome sequence analysis [17][18][67,68]. The majority of the cyclic peptides found in marine cyanobacteria are cyclic depsipeptides, which include 76 different molecules [19][69]. Two linear depsipeptides known as grassystatins A and B, have been isolated from the key Largo collected marine cyanobacterium Okeania lorea (formerly Lyngbya cf. confervoides). Veraguamides K and L, two linear bromine-containing depsipeptides isolated from the marine cyanobacterium cf. Oscillatoria margaritifera found in the Coiba Island National Park in Panama, are thought to have the structural characteristics of marine natural products [20][70]. The antimalarial bioassay-guided isolation of the marine cyanobacterium Moorea producens (formerly Lyngbya majuscula) yielded four lipopeptides: dragonamides A and B, carmabin A, and dragomabin [21][49]. Through the cytotoxicity-directed isolation of a marine cyanobacterium, the Symploca cf. hydnoides sample from Cetti Bay (Guam), seven novel cyclic hexadepsipeptides, known as veraguamides A–G, were discovered [22][23][71,72]. HT29 colorectal adenocarcinoma and HeLa cell lines exhibited moderate-to-mild cytotoxicity in response to these compounds [24][73]. Lyngbya majuscula has been proven to be a highly prolific species of cyanobacterium since a significant number of natural products with a wide range of structural characteristics have been isolated from it. The antimycobacterial cyclodepsipeptides known as pitipeptolides C–F were discovered from the marine cyanobacterium Lyngbya majuscule in the Piti Bomb Holes (Guam) [25][74]. Hoiamide A is an unusual cyclic depsipeptide that was isolated from the marine cyanobacteria Lyngbya majuscula and Phormidium gracile in Papua New Guinea. It is composed of an isoleucine moiety that has been modified by acetate and S-adenosyl methionine, a tri-heterocyclic fragment which contains two α-methylated thiazolines and one thiazole ring. 

3. Mechanistic Insights

3.1. Apoptosis

Apoptosis is an essential mechanism of cell death induced by cancer therapy. Therefore, identifying or developing anticancer agents capable of targeting apoptosis regulatory genes is a prerequisite for the advancement of unique anticancer therapies. As with most anticancer agents, there are a large number of marine-derived anticancer peptides with apoptotic activity in cancer cells [26][27][76,77]. The discharge of cytochrome-c (cyt c) activates caspases and triggers apoptosis [28][29][78,79]. Cyclolaxaphycins B and B3 increase caspase 3 in SH-SY5Y lines with IC50 of 1.8 and 0.8 µM, respectively (Figure 1) [30][61]. Coibamide A induces apoptosis in Neuro-2a cells (IC50 < 23 nM) through caspase-3,7 activation, cyt-c release and PARP cleavage. In U87-MG and SF-295 glioma cells, coibamide A triggered caspase-3/7 activation over a time-period associated with a loss of viability, although the activation profile for each cell line was different. Despite the fact that the MTT cell viability experiments showed that U87-MG cells were more sensitive than SF-295 cells to coibamide A-induced cell death, relatively large doses of coibamide A were required to cause the late activation of caspase-3/7 in these cells. Over a 96 h exposure period, researchers collected attached and detached coibamide A-treated cells and examined cell lysates for the expression of PARP1, a critical downstream target of caspase-dependent apoptosis, as well as a number of alternative cell death pathways [31][32][33][38,57,58].
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Figure 1. Cyanobacterial metabolites disrupt vital cancer-related pathways. Cyclolaxaphycins B and B3 increase caspase 3 and stimulate apoptosis. Somocystinamide A stimulates caspase-8 activation in Neuro-2a cells. Ub; ubiquitin protein.
Optic atrophy 1 (OPA1) is a crucial molecule in cancer cell biology and therapeutic resistance. OPA1 determines the mitochondrial resistance to cytochrome c release and delays apoptosis. The induction of OPA1 is required to alter gene expression during angiogenesis. It has also been identified as an essential regulator of lymphangiogenesis. Due to its dual role in angiogenesis and lymphangiogenesis, targeting OPA1 not only inhibits tumor development but also metastatic spread [34][82]. 
Musashi-2 (MSI2) is expressed in NB, and its decreased expression is related to increased apoptosis and decreased proliferation [35][85]. The inhibition of the histone deacetylase (HDACi) causes apoptosis induction, PARP cleavage, and G1 or G2/M cell cycle arrest in NB cells [36][86]. Largazole inhibits IMR-32 cell proliferation with a GI50 (growth inhibitory power of the test agent) of 16 nM and SH-SY5Y with an IC50 of 102 nM by decreasing the MSI2 levels, suppressing the mTOR pathway, and HDACi [37][38][39][41,59,60].

3.2. Cell Cycle Arrest

Cell cycle interruption prevents cancer cells from developing into tumor cells and spreading to other parts of the body [40][87]. Grassypeptolides D and E, ibu-epidemethoxylyngbyastatin 3, and dolastatin 12 from Leptolyngbya sp. induce G2/M phase arrest in Neuro-2a cancer cells [41][39]. Similarly, coibamide A from Leptolyngbya sp. induce G1 to S phase arrest [33][58].

3.3. Sodium Channel Blocking Activity

The voltage-gated sodium channel (VGSC) is widely expressed in breast, bowel, prostate cancers, melanoma and NB. Several VGSCs-blocking drugs have been shown in preclinical models to limit cancer cell proliferation, invasion, tumor development, and metastasis, indicating that VGSCs may serve as putative molecular targets for cancer therapy [42][43][88,89]. Malyngamides C, J, and K were shown to block VGSCs in Neuro-2a cells displaying IC50 0.49–4 μg mL−1 [44][47].

3.4. Antimetastatic Activity

Microfilaments play an essential role in cell migration. The inhibition of actin polymerization disrupts microfilaments, reduces the cell motility, and slows the metastatic spread of neoplastic cells by G2/M phase arrest [45][46][90,91]. Microtubules and microtubule-associated proteins, which play a vital role in cell division, are essential constituents of the mitotic spindle. Microtubule dynamics is necessary for chromosomal movement throughout anaphase. A shift in the tubulin-microtubule balance alters the mitotic spindle, disrupting metaphase-anaphase progression of the cell cycle, resulting in cell death [47][48][92,93]. Microtubule-stabilizing compounds stimulate microtubule polymerization and, by binding to microtubules, target the cytoskeleton and spindle machinery of tumor cells, thus limiting mitosis [47][49][92,94]. Aurilide B-C, a cyclodepsipeptide isolated from Lyngbya majuscula, has been shown to destabilize microtubules in Neuro-2a cells with an IC50 of 0.01 and 0.05, μM, respectively [50][30]. STAT3 suppression induces apoptosis and inhibits metastasis in cancer cells. MMP2 and MMP9 are upregulated when the STAT3 pathway is activated, facilitating tumor invasion [51][97]. Apratoxin A is proposed to inhibit the phosphorylation of the signal transducer and activator of transcription (STAT) 3, causing metastasis in Neuro-2a cells with an IC50 of 1 µM [52][53][42,98]. Proteases are critical signaling molecules engaged in a variety of key processes such as apoptosis, metastasis and angiogenesis [54][55][56][99,100,101]. Serine proteases are highly expressed in NB [57][102]. Numerous cyanobacterial peptides have been shown to interfere with serine protease functions.

3.5. Antiangiogenic Effect

VEGF and MMPs play an essential role in angiogenesis [58][59][104,105]. Angiogenesis is believed to be a fundamental prerequisite for the development, invasion, and metastasis of malignant NBs. Anti-angiogenic agents that inhibit neovascularization could represent a potential therapeutic strategy for NB [60][106]. The marine peptide coibamide A inhibits cancer cell migration by lowering the VEGFR2 and MMP-9 expressions [32][33][57,58].

3.6. Autophagy

In the early stages of cancer, autophagy functions as a barrier to protect cells against damaging stimuli and malignant development [61][62][107,108]. The activation of mTOR inhibits autophagy induction and promotes tumor growth and metastasis (Figure 23). Therefore, the regulation of autophagy with mTOR inhibitors provides an anticancer effect [63][109]. AMPK activates the autophagy-initiating kinase Ulk1 and phosphorylates TSC2. TSC2 activation can inhibit the mTOR complex 1 (mTORC1), thus promoting autophagy [64][110].
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Figure 23.
Cyanobacterial peptides involved in the activation of mTOR autophagy.

3.7. Unknown Mechanisms for Anticancer Activity

Several peptides including floridamide [65][55], guineamides B–C and G [66][67][32,33], hermitamides A–B [68][45], hoiamide A [69][36], jamaicamides A–C [70][46], and tiahuramides B–C [71][34], isolated from Lyngbya majuscula, bouillonamide [52][42], ulongamide A [52][42], isolated from Lyngbya bouillonii (now called Moorea bouillonii) [72][111]; wewakpeptin A–D [73][56] isolated from Lyngbya semiplena; dragonamides C and D [21][49], microcolin A–B, and desacetylmicrocolin B [74][50] isolated from Lyngbya polychroa all display significant cytotoxicity, though their specific modes of action have yet to be characterized. References

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