# A systematic review on calothrixins: potential cyanobacterial metabolites from chemistry to pharmacological properties, synergism and safety aspects

Abhishek Chauhan, Vinay Mohan Pathak, Ritu Chauhan, Seeta Dewali, Satpal Singh Bisht, Neelesh Babu, Anuj Ranjan, Naveen Chandra Joshi, Laurent Dufossé

► To cite this version:

Abhishek Chauhan, Vinay Mohan Pathak, Ritu Chauhan, Seeta Dewali, Satpal Singh Bisht, et al. "A systematic review on calothrixins: potential cyanobacterial metabolites from chemistry to pharmacological properties, synergism and safety aspects." Results in Chemistry, 2025, 18, pp.102844. 10.1016/j.rechem.2025.102844. hal-05509429

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# A systematic review on calothrixins: potential cyanobacterial metabolites from chemistry to pharmacological properties, synergism and safety aspects

Abhishek Chauhan<sup>a, *,</sup>, Vinay Mohan Pathak<sup>b</sup>, Ritu Chauhan<sup>c</sup>, Seeta Dewali<sup>d</sup>, Satpal Singh Bisht<sup>d</sup>, Neelesh Babu<sup>e</sup>, Anuj Ranjan<sup>a</sup>, Naveen Chandra Joshi<sup>f</sup>, Laurent Dufossé<sup>g, *</sup>

## ARTICLE INFO

### Keywords:

Anticancer

Antifungal

Cyanobacteria

Synthesis. Antidiabetic

Nanotechnology

## ABSTRACT

Calothrixins, bioactive secondary metabolites derived from the cyanobacterium *Calothrix*, have gained significant interest owing to its wide range of pharmacological properties. Anti-cancer, antimicrobial, antidiabetic and other therapeutic properties of this compound make it novel and unique. In the present article, the existing knowledge pertaining to the pharmacological properties of the calothrixins has been compiled based on its studies.

Calothrixins A and B have been reported to be cytotoxic against a wide variety of cancer cell lines, especially the breast, lung, and colon cancer cell lines, by DNA intercalation leading to apoptosis. In combination with other drugs, the efficiency of treatment and the reduction of harmful side effects have also been enhanced by overcoming drug resistance. In addition to its anticancer properties, calothrixins are promising broad-spectrum antibacterial and antifungal agents for use in the treatment of antibiotic-resistant infections. These molecules have recently been prepared by advances in synthetic chemistry, which reveal its characteristic polycyclic structures and the reactivity confirming its biological activity.

In this review, an insightful discussion has been provided on improving the calothrixins delivery and efficacy using nanotechnology, along with safety concerns due to its toxicity and pro-oxidant activity. To infer, calothrixin compounds are promising in pharmacological and drug development, which would enable multifaceted approaches toward the development of novel medications against various health challenges.

## 1. Introduction

Calothrixins are a class of secondary metabolites derived from the filamentous cyanobacterium *Calothrix*, known for its pharmacological properties in various therapeutic areas, particularly in oncology. Specifically, calothrixin A and B are most studied and researched because of its unique structures and potential biological activities [1]. Calothrixins have shown significant cytotoxic activity against different types of malignant cell lines viz., breast, lung, and colon cancer cell lines. The most important method through which calothrixins exert its anticancer effects is programmed cell death (apoptosis) in malignant cells via the

intercalation of calothrixins into DNA, which causes DNA damage and leads to cell cycle arrest or cell death [2]. The apoptosis targets malignant cells, which are more susceptible to DNA damage because of its rapid division. Such discriminating cytotoxicity is beneficial in cancer therapeutics because it minimises damage to healthy tissues.

Further vital use of calothrixins in cancer treatment is its ability to overcome drug resistance [3]. Over time, cancer cells develop resistance to conventional chemotherapies, rendering these treatments unsuccessful. Calothrixins have a different mode of action, which bypasses the pathways involved in resistance to supplementary drugs. Such ability to prevent drug resistance makes calothrixins a significant component of

<footnote><sup>a</sup> Amity Institute of Environmental Toxicology Safety and Management, Amity University, Noida, U.P., India</footnote>

<footnote><sup>b</sup> Parwatiya Shiksha Sabha (PASS), Near Transport Nagar Develchaur Kham, Haldwani, Nainital 263139, India</footnote>

<footnote><sup>c</sup> Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun 248002, Uttarakhand, India</footnote>

<footnote><sup>d</sup> Department of Zoology, Kumaun University, Nainital, India</footnote>

<footnote><sup>e</sup> Department of Microbiology, School of Allied Sciences, Devbhoomi Uttarakhand University, Dehradun 248007, India</footnote>

<footnote><sup>f</sup> Amity Institute of Microbial Technology, Amity University, Noida 201313, India</footnote>

<footnote><sup>g</sup> Chemistry and Biotechnology of Natural Products, CHEMBIOPRO, Université de La Réunion, ESIROI Agroalimentaire, 15 Avenue René Cassin, CS 92003, CEDEX 9, F-97744 Saint-Denis, France</footnote>

<footnote>* Corresponding authors.</footnote>

<footnote>E-mail addresses: akchauhan@amity.edut (A. Chauhan), laurent.dufosse@univ-reunion.fr (L. Dufossé).</footnote>
combination therapies, enhancing the overall effectiveness of treatment regimens [4].

Calothrixins have synergistic effects when it is used in combination with other chemotherapeutic agents which improves the efficiency of other drugs, allowing for lower doses and thus decreasing side effects associated with high-dose chemotherapy. This makes calothrixins mainly useful in multidrug treatment therapy, where they contribute to a more effective and less toxic therapeutic approach [5]. Calothrixins have also been verified to have antimicrobial effects, including anti-bacterial and antifungal effects. Such antimicrobial potential makes calothrixins promising candidates for the development of new antimicrobial compounds for infectious diseases, particularly those caused by antibiotic-resistant bacteria and fungi [6]. As the rise of antibiotic resistance is a significant global public health concern, new compounds such as calothrixins could play a crucial role in addressing this issue.

While most research on calothrixins has been conducted in preclinical settings, involving both in-vitro (cell culture) and in-vivo (animal model) studies, these studies have provided a strong background for understanding the therapeutic potential. Several challenges need to be addressed to realize the full potential of calothrixins in medical applications. For instance, calothrixins to transition from promising preclinical agents to clinically viable drugs, there must be rigorous pharmacological studies and clinical trials [7]. These trials will evaluate its safety, efficacy, optimal dosing, and potential side effects in humans.

Another significant concern is its toxicity profile. Although calothrixins have shown selective toxicity against cancer cells, its effectiveness on normal cells and overall safety profile evaluation is essential. Effective drug delivery systems are also crucial for increasing the therapeutic potential of calothrixins [8]. Advances in targeted delivery methods, such as nanoparticles or conjugates, could enhance the selective delivery of calothrixins to specific sites in the body, reducing systemic exposure and associated side effects. The present review article aims to provide a critical overview of the existing knowledge on

calothrixins with respect to its physicochemical and, pharmacological properties, and possible therapeutic applications by synthesizing findings from several studies. The article also highlights the mechanisms underlying its biological effects and explores future prospects in drug development. The article also highlights the importance of calothrixins for the development of therapeutic strategies and to identify key areas for further research to fully realize its potential in clinical applications.

## 2. Methodology

### 2.1. *Search strategy*

For the research document search strategy, we included data from 1992 to 2024. The literature was chosen through a search in electronic databases such as PubMed, ScienceDirect, SpringerLink, Wiley Online, Web of Science, and Scopus with the following terms: "Calothrixins" then paired with "Chemistry," "Synthesis," "Pharmacological Activities," "Biological Evaluation," "Medicinal use," "Biological activities," "Antibacterial activity," "Antifungal activity," "Minimum Inhibitory Concentration," "Antiviral activity," "Antiparasitic activity," "Anticancer activity," "Antiproliferative action," "DNA damage," "Apoptosis," "Cell Cycle Arrest," "Inhibiting Cell Migration," "Antidiabetic," "Antimetagenic activity," "In-vivo study," "Antimetagenic activity," "Synergism," and "Safety Aspects". No language restrictions were applied. The papers were carefully reviewed (Fig. 1). The following are the inclusion and exclusion criteria.

### 2.2. *Inclusion and exclusion criteria*

The inclusion criteria were as follows: a) pharmacological and biological activities of Calothrixins; b) *Calothrix* sp. biomass, crude extracts, fractions, isolated compounds, semisynthetic, synthetic preparations or derivatives; d) studies including preliminary or advanced investigations

<figure><img src="image_2.png" /><figcaption>**Fig. 1.** PRISMA flow diagram illustrating the systematic review process. The diagram provides the number of publications identified, screened, excluded, and ultimately included, providing a transparent overview of the study selection workflow.</figcaption></figure>
of Calothrixins and its pharmacological properties; e) studies examining the chemical features of Calothrixins and its biological activities, including antibacterial, antifungal, antiviral, antiparasitic, anticancer, antiproliferative, antidiabetic, and antimutagenic activities; and f) studies that explored the role of nanotechnology, synergistic effects, and safety features of Calothrixins.

The exclusion criteria were as follows: i) studies on compounds derived from sources other than *Calothrix* spp.; ii) in-vitro studies whose title and abstract did not fit the inclusion criteria; iii) any research other than Calothrixins; iv) studies for which the full text was not available; v) case reports, letters, editorials, and commentaries.

### 3. Chemistry of calothrixins

Calothrixins, such as calothrixins A and B, are natural compounds with amazing biological activities due to its unique chemical structure [9]. These compounds are produced by the cyanobacterium *Calothrix*, but they are different from the other compounds of the same genus because they are polycyclic, connecting indolo [3,2-j] phenanthridine with a quinone moiety [10]. The molecular formula of calothrixins B is C20H14N2O2, whereas calothrixin A has a slightly higher oxidation state with an additional hydroxyl group, with a molecular formula of C20H14N2O3. It is very challenging to synthesize simple aromatic base compounds. Owing to its complexity, they include quinone incorporation, cyclization of polycyclic cores, and indole ring synthesis. Although all functional groups need to be placed correctly according to the criteria of biological activity, achieving high yield purity cannot be guaranteed, as the reaction conditions are sensitive [11].

Two bioactive strains of *Calothrix* produced active extracts, and fractionation via bioassays revealed the presence of insoluble calothrixin A and its more soluble co-metabolite (simultaneous degradation of two compounds, in which the degradation of the second compound -the secondary substrate- depends on the presence of the first compound (the primary substrate), calothrixin B [12]. Over the past few years, new synthesis methods have been developed to achieve large-scale production of calothrixins. Synthesis methods are categorized into three main groups on the basis of the last ring closure step in scaffold construction (Xu et al., 2014b). The chemical reactivity of quinones mostly depends on its functional groups, which govern how many different types of reactions each molecule can potentially undergo; for example, quinones possess special reactivity owing mainly to its redox properties, being capable of undergoing nucleophilic additions and other related transformations. Moreover, the polycyclic aromatic system can engage in aromatic substitution reactions, although steric hindrance may influence these processes [13]. Additionally, the hydroxyl group in calothrixin B further enhances reactivity; hence, it can undergo oxidation as well as esterification (Fig. 2). Notably, such chemical characteristics determine the biological activities of calothrixins, which include the ability to intercalate with DNA molecules and the inhibition of

topoisomerase enzymes, thus disrupting DNA function and replication, especially in cancerous cells [14]. Additionally, the redox potential of quinone generates reactive oxygen species that lead to oxidative stress, thereby contributing to the antimicrobial and anticancer effects of calothrixins [2].

So far, scientists have synthesized calothrixins on the basis of different mechanisms at different times. The retrosynthetic analysis of calothrixin B is an oxidative free radical reaction strategy. In this regard, the most important steps include the amination of 2,4,5-trimethoxybenzaldehyde with *ortho-iodoaniline*, followed by palladium-catalyzed coupling. Subsequent oxidation by CAN (ceric (IV) ammonium nitrate) and, finally, an oxidative free radical reaction with cyclohexenone in the presence of Mn(OAc)3. This strategy, in which the indole ring is constructed into the phenanthridine dione via a unique novel approach, leads to the synthesis of calothrixin B, which further undergoes oxidation to form calothrixin A (Xu et al., 2014a; Fig. 2). (See Fig. 2.)

The synthesis of calothrixin B has been achieved within 5 steps from murrayaquinone A, wherein boryl aniline and brominated murrayaquinone A are involved in a key step through tautomerization to quinone methide, C-N bond formation, intramolecular Suzuki coupling, and dehydrogenative aromatization. Further N-oxidation of calothrixin B yielded calothrixin A, which completed the total synthesis and set the path for all basic challenges ([16]; Fig. 3).

The bioactive alkaloid calothrixin B was created from commercially accessible starting materials. A Baylis-Hillman/6π electrocyclization/dehydroaromatization step was crucial for establishing the pentacyclic structure. After oxidation and reduction of the resulting lactam, a distinctive quino[4,3-b]carbazole structure was produced. The final product is obtained via high regioselectivity direct oxidation of this intermediate ([17]; Fig. 4).

Consequently, in addition to defining its level of complexity in terms of structure, the chemistry of these compounds supports various important biointeractions, making them quite useful in both studies and potential therapies.

### 4. Pharmacological potential of calothrixins

In the past few decades, numerous studies have explored and identified the biotechnological and pharmaceutical effects of metabolites derived from cyanobacteria. However, calothrixins have been a leading research interest. The studies have revealed various pharmacological properties, viz., anticancer, anti-inflammatory, antimalarial, antiprotozoal, antimicrobial, immunosuppressant, antibacterial, and antiviral properties (Fig. 5) [18].

In recent decades, the emergence of new cancers and its increasing resistance to drugs has led to the failure of chemotherapeutics. Consequently, the detection of novel metabolically active compounds is immediately needed for the development of new chemotherapeutics [19]. Therefore, the therapeutic potential of cyanobacteria has been

<figure><img src="image_3.png" /><figcaption>**Fig. 2.** Chemical structures of calothrixins. Structural representations of (a) Calothrixin A and (b) Calothrixin B, two indolophenanthridine alkaloids isolated from the cyanobacterium *Calothrix*, which exhibit significant biological and pharmacological activities.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Synthetic pathway of Calothrixin B as reported by Xu et al. [15]. The figure illustrates the stepwise chemical reactions and intermediates employed in the laboratory synthesis, highlighting the strategies used to construct the indolophenanthridine core structure.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 3.** Alternative synthetic approach to Calothrixin B described by Mori-Quiroz et al. [16]. The scheme outlines the reaction sequence, key reagents, and conditions, providing insights into the efficiency and versatility of this synthetic route.</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>**Fig. 4.** Retrosynthetic analysis of Calothrixin B [17]. The figure depicts the retrosynthetic disconnection strategy, tracing back from the target molecule to simpler precursors, thereby demonstrating the logic and feasibility of synthetic design.</figcaption></figure>

explored. The ability of Cyanobacteria to incorporate nonribosomal peptides with polypeptide syntheses enables them to fabricate chemically diverse as well as biologically active compounds, such as cyclic alkaloids, peptides, depsipeptides, cyclic depsipeptides, fatty acids, lipopeptides, swinholides and saccharides [20]. Thus, metabolites derived from cyanobacteria have the potential to favor expanded consumption in drug innovation (Singh et al., 2013). Despite its potent biological activities, very few cyanobacteria compounds have entered medical trials; one of the reasons is the complication in the synthesis of natural products. A vast array of secondary metabolites, frequently with a distinct composition and specialized roles, are produced by cyanobacteria and arbitrate a multiplicity of actions, chemical defenses, preservation and quorum sensing (Kar et al., 2022).

### 4.1. Antibacterial activity

Calothrixins have broad-spectrum antimicrobial properties, which make them candidates for new antibacterial drug research, addressing the urgent need for effective treatments against strains of bacteria [6]. Therefore, extracts of *Calothrix* sp. and calothrixins have presented outstanding antibacterial activities against different pathogenic bacteria, indicating that such sources are very promising for combating antibiotic-resistant infections. Calothrixins have shown activity against methicillin-resistant *Staphylococcus aureus*, a critical problem in clinical settings [13]. The chloroform extracts of *Calothrix* sp. showed broad-spectrum activity against *Bacillus subtilis*, *Staphylococcus aureus*, *Escherichia coli*, and *Klebsiella pneumoniae* [21]. Ethanolic extracts also target
<figure><img src="image_7.png" /><figcaption>**Fig. 5.** Different pharmaceutical potential of the cyanobacteria bioactive compound calothrixins.</figcaption></figure>

*Staphylococcus aureus* [22]. Calothrixin A from *Calothrix* sp. has selective activity against *Bacillus subtilis* [23]. The antibacterial activities of the *Calothrix* extracts and calothrixins described in Table 1 reveal that they

<table><caption>**Table 1**
Antimicrobial Activity of *Calothrix* Extracts and Calothrixins.</caption><thead><tr><th>Compound/ Extract</th><th>Target Microorganism(s)</th><th>Reported Activity</th><th>Reference</th></tr></thead><tbody><tr><td>Calothrixins</td><td>Methicillin-resistant Staphylococcus aureus</td><td>Antibacterial</td><td>[13]</td></tr><tr><td>Chloroform extract of Calothrix sp.</td><td>Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae</td><td>Antibacterial</td><td>[21]</td></tr><tr><td>Ethanolic extract of Calothrix sp.</td><td>Staphylococcus aureus</td><td>Antibacterial</td><td>[22]</td></tr><tr><td>Calothrixin A (Calothrix sp.)</td><td>Bacillus subtilis</td><td>Antibacterial</td><td>[23]</td></tr><tr><td>Calothrix brevissima</td><td>Staphylococcus aureus, Escherichia coli, Candida albicans</td><td>Antibacterial, Antifungal</td><td>[13]</td></tr><tr><td>Calothrix elenkinii extract</td><td>Escherichia coli, Pseudomonas aeruginosa</td><td>Antibacterial</td><td>[31]</td></tr><tr><td>Calothrix javanica extract</td><td>Aspergillus niger, Trichophyton capitanum, Aspergillus flavus, Fusarium moniliforme, Helminthosporium sp., Alternaria sp., Candida albicans</td><td>Antifungal</td><td>[32]</td></tr><tr><td>Calothrix elenkinii extract</td><td>Pythium debaryanum</td><td>Antifungal</td><td>[31]</td></tr><tr><td>Calothrix sp. Extract</td><td>Rhizoctonia bataticola, Pythium debaryanum</td><td>Antifungal</td><td>[33]</td></tr><tr><td>Calothrix sp. Extract</td><td>Alternaria alternata, Botrytis cinerea</td><td>Antifungal</td><td>[34]</td></tr><tr><td>Calothrix fusca extract</td><td>Aspergillus oryzae, Candida albicans, Penicillium notatum, Saccharomyces cerevisiae, Trichophyton mentagrophytes</td><td>Antifungal</td><td>[35]</td></tr><tr><td>Calothrix gracilis extract</td><td>Influenza A virus</td><td>Antiviral</td><td>[36]</td></tr><tr><td>Calothrixin A and B</td><td>Plasmodium falciparum (FCR-3 strain)</td><td>Antiparasitic</td><td>[12]</td></tr></tbody></table>

are potent against a variety of pathogenic bacteria. Potential mechanisms of action of the antibacterial properties of *Calothrix* extracts and calothrixins involve several ways of disrupting the integrity of bacterial cell membranes, which causes cellular leakage that eventually leads to cell death. The antibacterial activity could also result from the inhibition of some essential bacterial enzymes or its metabolic pathways. The compounds may bind to bacterial DNA or RNA and thereby inhibit replication and transcription. All these mechanisms have yet to be elucidated; however, the observed antibacterial activity suggests a therapeutic role for *Calothrix*-derived substances against resistant bacterial strains.

## 4.2. Antifungal activity

Calothrixins, particularly calothrixin B, demonstrate a wide range of antifungal activities and can be used against human diseases. The bisindole alkaloid calothrixins, which are found in marine cyanobacteria, are known for its ability to target many different types of microbes, including fungi. They have been used to disrupt the growth of fungal organisms via several biological mechanisms that have been demonstrated in various experiments on pathogenic fungi. Therefore, its potential as an antifungal drug candidate has been identified [6]. The antifungal properties of calothraxins are quite effective because they can disrupt the integrative and functional capabilities of fungal cells. This is particularly relevant in the context of increasing fungal resistance to conventional antifungal agents. The potent activity of calothrixins is due to its molecular structure, which allows them to affect the cells of the fungi and thus stop its growth [24]. Cyanobacteria are the natural source of calothrixins, and studies have highlighted the advantages these compounds have over synthetic antifungal medicines in terms of sustainability and ecology. These findings support the continuous search for safe and potent antifungal drugs that are not harmful to the environment. Research on calothrixins is still being conducted to fully investigate its potential and address the global problem of fungal infections, which are becoming more difficult to treat because of resistance challenges [25]. The antifungal activities of *Calothrix* extracts and calothrixins, summarized in Table 1, are effective against a range of fungal pathogens.

## 4.3. Antiviral activity

The extract of calothrixins, especially calothrixin B (obtained from the marine cyanobacterium *Calothrix*), is characterized by marked antiviral properties. These carbazole alkaloids are not only bioactive toward all antigens but also carry out antitumor activities. Calothrixins have exceptional antiviral properties by interrupting viral replication processes and blocking viral protein functions; therefore, it deserve to be considered among the candidates for antiviral drug development. The antiviral properties of calothrixins are well recognised, with the growing trend of exploring natural products, which have high potential for activity and are often less toxic than synthetic drugs [5,13]. Studies have highlighted the discovery of various antiviral cyanobacterial toxins, which have attracted the attention of the marine bioactive community, as these extracts can treat viral infections. These studies highlight the need for further exploration and development of new classes of antiviral agents against viral infections [25]. Given the emerging resistance to conventional antiviral drugs and the urgent need for novel therapeutics, Calothrixins present a valuable area for future research and drug development [26,27].

## 4.4. Antiparasitic activity

*Calothrix* produces unique secondary metabolites with high biological activity, which contribute significantly to interest in its antiparasitic properties. These metabolites disrupt various parasites' life cycles, reducing its virulence and survival. The antimalarial characteristics of
*Calothrix* are attributed to chemicals that interfere with the parasite's capacity to synthesize proteins and sustain mitochondria, eventually leading to its death [28]. *Plasmodium falciparum*, a malaria parasite resistant to chloroquine, is inhibited in-vitro in a dose-dependent manner by cell extracts from photoautotrophic cultures of two Cyanobacterial *Calothrix* isolates. Calothrixins A and B have an indolo[3,2-j] phenanthridine ring structure that is unique among natural products [12]. Calothrixins A and B also inhibited the FAF6 strain of *P. falciparum*, with $IC_{50}$ values of approximately 60 and 180 nM, respectively [29]. N-alkyl derivatives of calothrixins A and B were synthesized by [30] who further studied their in-vitro antimalarial efficacy against the *P. falciparum* FCR-3 strain was assessed [30].

## 4.5. Anticancer activity

Calothrixins are quinone-based bioactive molecules isolated from *Calothrix* that have potent antiproliferative effects on several cancer cell lines [37]. Calothrixin A, an indolophenanthridine has been reported to induce programmed cell death and cell cycle arrest in the G2/M phase during the cell cycle in several cancer cell lines (Table 2). It has been shown to have antitumor effects on human HeLa cancer cells at nanomolar concentrations [38]. Furthermore, calothrixin B exhibited anti-proliferative action against the HCT-116 colon cancer cell line, with an $IC_{50}$ value of 0.32 M [39]. The calothrixin B analogs, which slow cancer cell development through gradual suppression of DNA damage followed by programmed cell death, has been reported ([11]; Fig. 6). Specifically, Ramalingam et al. [11] demonstrated that the 3-fluorocalothrixin B analogue (15 h) exhibited low toxicity in vivo, while its deoxygenated derivative, 4-fluoroquinocarbazole (21b), displayed remarkable cytotoxicity against the NCI-H460 lung cancer cell line with a $GI_{50}$ value of 1 nM, emphasising the strong structure-activity relationship of these analogues.

<table><caption>**Table 2**
Anticancer Effects of Calothrixins on Different Cell Lines.</caption><thead><tr><th>Compound</th><th>Cancer Cell Line(s)</th><th>IC<sub>50</sub>/LC<sub>50</sub>/ED<sub>50</sub>/GI<sub>50</sub></th><th>Molecular Targets / Mechanism</th><th>Reference</th></tr></thead><tbody><tr><td>Calothrixin A</td><td>HeLa, HCT-116, NCI-H460</td><td>IC<sub>50</sub> = 0.32 µM; GI<sub>50</sub> = 1 nM</td><td>Cell cycle arrest in S and G2/M phases</td><td>[39]</td></tr><tr><td>Calothrixin B</td><td>HEL cells</td><td>IC<sub>50</sub> = 3.63 ± 0.33 µM</td><td>Downregulates Ras, p-Raf, p-MEK, p-ERK, and c-Myc; ERK inhibitor (U0126) pretreatment enhances apoptosis</td><td>[5]</td></tr><tr><td>Calothrixin A</td><td>Jurkat cells</td><td>IC<sub>50</sub> = 0.3 µM</td><td>~18% cell death within 24 h</td><td>[38]</td></tr><tr><td>Calothrixin A</td><td>A549, NCI-H1650</td><td>IC<sub>50</sub> = 110 nM (A549), 230 nM (NCI-H1650)</td><td>Inhibits Topo I activity; arrests cell cycle at S phase; reduces A549 cell migration via MMP-2/9 inhibition</td><td>[40]</td></tr><tr><td>Calothrixin A</td><td>A375, HCT116</td><td>IC<sub>50</sub> = 20 nM (A375), 50 nM (HCT116)</td><td>Inhibits Topo I and II; arrests cell cycle; potent anti-proliferative</td><td>[10]</td></tr><tr><td>Calothrixins A &amp; B</td><td>CMC leukemia cells</td><td>IC<sub>50</sub> = 0.20-5.13 µM</td><td>Cell accumulation in S and G2/M phase</td><td>[41]</td></tr><tr><td>Calothrixin B</td><td>Leukemia cell lines HEL, K562, KG-1a</td><td>IC<sub>50</sub> = 1.10 ± 0.05 µM (HEL), 5.46 ± 3.09 µM (K562), 1.82 ± 1.08 µM (KG-1a)</td><td>Induces mitochondrial-mediated apoptosis and G2/M arrest via DNA damage and p38 MAPK pathway modulation</td><td>[42]</td></tr></tbody></table>

Isothiacalothrixin B, another analog of calothrixin B, has shown cytotoxicity to colon cancer cells in an in vitro study, because irreversible DNA damage eventually causes the apoptosis of colon cancer cells. It was established to be a promising anticancer agent that strongly arrested the cells in the S and G2/M phases of the cell cycle in the HCT116 cell line [2].

Acute erythroleukemia (AEL) is acute myeloid leukemia characterized by malignant erythroid proliferation. AEL has a low survival rate and is critically dangerous to the health of older adults. Calothrixin B is a carbazole alkaloid isolated from the cyanobacteria *Calothrix* and exhibits anticancer activity [5]. In addition to potent in vitro activity, the optimized analogue F16 significantly reduced tumor growth in xenograft models at doses of 10-20 mg/kg without observable toxicity, whereas the clinically used Topo II inhibitor VP-16 caused marked weight loss in treated mice [10].

## 4.6. Antidiabetic and Antimetagenic activity

In terms of its antidiabetic activity, calothrixins improve insulin sensitivity, improving the body's response to insulin and facilitating glucose uptake by cells, thus lowering blood sugar levels [43]. They also inhibit alpha-glucosidase, an enzyme that breaks down carbohydrates into glucose, thereby slowing glucose absorption in the intestines and reducing postprandial blood sugar spikes. Furthermore, calothrixins may stimulate insulin secretion from pancreatic beta cells, promoting better regulation of blood glucose levels [44].

In terms of antimutagenic activity, calothrixins protect DNA from damage caused by mutagenic agents such as radiation and chemical carcinogens owing to its antioxidant properties, which reduce oxidative stress by scavenging free radicals. Its strong antioxidant activity is achieved not only by scavenging free radicals but also by reducing overall oxidative stress and increasing the activity of endogenous antioxidant enzymes such as superoxide dismutase and catalase [45]. Such multifaceted antioxidant action contributes significantly to protecting cells from oxidative damage, which is linked to aging, cancer, and various chronic diseases.

To sum up, the diverse pharmacological activities of calothrixins make them promising candidates for various therapeutic applications. The antidiabetic, antimutagenic, antioxidant, neuroprotective, and anti-inflammatory properties of these compounds highlight its potential in addressing multiple health conditions. Further research is essential to fully elucidate its mechanisms and optimize the clinical use would pave the way for the development of new therapeutic strategies based on these versatile compounds.

While calothrixins display promising biological activities, recent evidence is mostly limited to in vitro assays, with limited in vivo validation, which restricts its translational potential. In contrast, natural products such as camptothecin, a plant-derived topoisomerase I inhibitor, have progressed into clinically approved drugs (e.g., topotecan, irinotecan), owing to extensive in vivo and clinical data [46]. Calothrixins act as reversible topoisomerase I poisons [41], which may represent a safety advantage compared to the irreversible action of camptothecin derivatives, but this needs further validation. Comparative evaluations with other cyanobacterial metabolites (e.g., scytomemin, caulerpin) and broader cyanobacterial-derived scaffolds indicate that while calothrixins may offer high potency in certain assays, its translational positioning requires direct efficacy and safety comparisons with these scaffolds (Kar et al., 2022; [6]).

### 1. Role of nanotechnology and synergism

Nanotechnology may enhance the delivery system for calothrixins by increasing its stability and solubility. The anticancer properties of calothrixins and nanotechnology can be used for targeted delivery to tissues to minimize adverse effects. Moreover, the controlled release of calothrixins may be achieved to maintain the optimal drug level.
<figure><img src="image_8.png" /><figcaption>**Fig. 6.** The Anticancer Mechanisms of calothrixin: Promoting Apoptosis and Cell Cycle Arrest and Inhibiting Cell Migration by suppressing MMP-2 and MMP-9 to inhibit cell migration and induces S-phase arrest to halt proliferation and modulates signaling by downregulating p-Akt and upregulating p-JNK, thereby activating Bax and Bad while inhibiting Bcl-XL and Bcl-2 leading to promotes cytochrome C release, activates caspase-9 and caspase-3, and triggers apoptosis, while also enhancing autophagy, collectively contributing to tumor suppression.</figcaption></figure>

Compared with mainstream drugs, nanoparticles can actively overcome biological barriers more effectively. Nanocarriers, such as liposomes, polymeric nanoparticles, or inorganic nanomaterials, can encapsulate calothrixins, improving its bioavailability and protecting them from premature degradation. Upon reaching tumor tissues, these nanocarriers release calothrixins in a controlled manner, allowing targeted action at the tumor site while reducing systemic toxicity. Such an approach would not only enhance the therapeutic efficacy of calothrixins but also address challenges related to its poor solubility and stability (Zhuo, Li, & Li, 2024; Edis, Wang, & Zhang, 2021). Synergistically, both nanoparticles and calothrixins enhance anticancer activity and may be used in combined therapies and reduce drug resistance, which leads to minimal side effects [47,48]. In cancer-related therapies, nanoformulation-based microalgal bioactive compounds tend to damage cancer cell integrity, which triggers the activation of the p53 protein, which functions as an activator of pro-apoptotic genes that tend to stimulate Bax, Bak and Bad proteins. These proteins are involved in mitochondrial membrane leakage, releasing cytochrome C and the activation of caspase-3 in a cascade reaction. The nuclear membrane is subsequently cleaved by Caspase-3. During this process, amplification of the apoptotic signal also takes place because the upregulation of C-myc actively acts as an inducer of apoptosis.

Similarly, the Bcl-2 and Bcl-XL, which are known to be anti-apoptotic genes, are downregulated, leading to cell blebbing [49]. Several compounds have important pharmacological activities, but due to its poor solubility, it is very difficult to develop formulations [50]. The formulation of these metabolites of marine algae with a nano-drug delivery system can be utilized to overcome such difficulties, and several inorganic materials (silica, carbon, metals and its oxides) can be used as suitable nanocarriers for drug delivery and stability [51,52]. The combination of calothrixins with nano-carriers enhances therapeutic efficacy by improving solubility, enabling controlled release, and ensuring tumor-specific targeting, which also helps in overcoming drug resistance. [53].

## 4.7. Safety Aspects

The toxicity of calothrixins poses potential challenges due to its

potent pharmacological properties [54,55]. Safety evaluation should consider pharmacological effects, cellular impacts, efficacy, and potential long-term health risks. Several studies have demonstrated the cytotoxic effects of calothrixins on various cell types, including inhibition of different phases of the cell cycle. Drew et al. (2002) reported that calothrixin B can arrest the G1 phase at a concentration of 0.1 µM, while higher concentrations result in accumulation in the S and G2/M phases [41]. Calothrixins also induce oxidative stress. Bolton et al. (2000) showed that calothrixin A exhibits redox activity in the presence of dithiothreitol, generating reactive oxygen species (ROS) that can damage cellular biomolecules upon prolonged exposure [37,42]. Calothrixins A and B have been shown to act as reversible DNA topoisomerase I poisons, inducing cytotoxicity in cultured leukemia cells with IC₅₀ values ranging from 0.20 to 5.13 µM [41]. Its effects on the cell cycle are largely reversible upon compound removal, suggesting a potentially controllable toxicity profile. Calothrixin B derivatives, such as the H-107 compound, have been shown to induce apoptosis and G0/G1 phase cell cycle arrest in HEL leukemia cells through mitochondrial-mediated mechanisms and modulation of the ERK/Ras/Raf/MEK pathway. H-107 exhibited an IC₅₀ of 3.63 ± 0.33 µM, significantly inhibiting proliferation and promoting erythroid differentiation in in vivo mouse models, highlighting both efficacy and potential for therapeutic application [5]. While calothrixins demonstrate promising anticancer activity, careful evaluation of its in-vitro and in-vivo safety profiles is crucial, which includes monitoring cell cycle perturbations, ROS generation, apoptotic pathways, and potential systemic effects to ensure safe progression into clinical applications.

## 5. Conclusions and further perspectives

Calothrixins represent a unique class of cyanobacterial metabolites with significant pharmacological potential. Its diverse bioactivities are linked to multiple mechanisms, such as DNA topoisomerase I poisoning, induction of oxidative stress, and modulation of apoptotic pathways. Recent studies also highlight its synergistic potential when combined with nanotechnology-based delivery systems, offering improved solubility, bioavailability, and targeted action. However, despite these promising findings, several research gaps remain. Current data are
largely limited to in vitro studies, with very few in vivo validations, and almost no clinical investigations, making translational relevance uncertain. Another key hurdle is the low natural yield of calothrixins from cyanobacteria, which necessitates efficient synthesis or semi-synthetic strategies to ensure a sustainable supply. Moreover, toxicity studies remain fragmented and lack long-term assessments, raising safety concerns for therapeutic applications. Regulatory considerations, such as pharmacokinetics, bio-distribution, and standardization of dosage, are yet to be systematically addressed. Future research should therefore focus on (i) expanding in vivo evaluations across diverse cancer models; (ii) optimizing scalable and eco-friendly synthetic pathways for calothrixin production; (iii) integrating nanocarrier systems for controlled delivery and reduced toxicity; and (iv) establishing regulatory frameworks and safety guidelines to accelerate clinical translation. In addition, comparative studies with existing chemotherapeutic agents are warranted to position calothrixins within the broader landscape of anticancer drug discovery.

## CRediT authorship contribution statement

**Abhishek Chauhan:** Writing – original draft, Visualization, Methodology, Investigation. **Vinay Mohan Pathak:** Writing – original draft, Validation, Methodology, Investigation. **Ritu Chauhan:** Writing – review & editing, Visualization, Validation. **Seeta Dewali:** Writing – review & editing, Validation, Formal analysis. **Satpal Singh Bisht:** Writing – review & editing, Validation. **Neelesh Babu:** Writing – review & editing, Methodology, Formal analysis. **Anuj Ranjan:** Writing – review & editing, Validation, Supervision. **Naveen Chandra Joshi:** Writing – review & editing, Validation, Supervision. **Laurent Dufossé:** Writing – review & editing, Validation, Supervision, Formal analysis.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Data availability

Data will be made available on request.

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