RETRACTED: Tiny bryophytes: nature's hidden reservoirs of powerful anti-cancer compounds

TL;DR

Tiny bryophytes contain powerful anti-cancer compounds that could serve as natural alternatives to traditional cancer drugs.

Contribution

The paper identifies and highlights potent anticancer compounds from bryophytes with proven efficacy against cancer cell lines.

Findings

Marchantin A, phytol, and perrottetin E show significant efficacy in inhibiting cancer cell lines.

Prenylated bibenzyls and phenanthrene demonstrate potential as anticancer agents.

Bryophytes are a promising natural source of less toxic anticancer compounds.

Abstract

Bryophytes are a promising source of bioactive compounds, offering a natural alternative to conventional anticancer drugs known for their cytotoxicity. This article highlights potent anticancer agents such as Marchantin A, phytol, perrottetin E, phenanthrene, and prenylated bibenzyls, which have demonstrated significant efficacy in inhibiting and destroying various cancer cell lines.

Figures

(A) Occurrence and habitat preferences of major bryophyte groups. Liverworts (Marchantia, Radula, Pellia, Riccia, Lunularia, Porella, and Lepidozia) flourish in cool, moist niches (10 to 25 °C); some grow in humid soils, rooftops, and alpine bogs, thriving at 5 to 20 °C. Mosses (Octoblephrum) grow in warmer, damp fields and rice paddies at 25 to 30 °C. Together, these bryophyte groups exhibit a remarkable ecological spread ranging from urban walls to mountain slopes and peat bogs, highlighting their adaptability to diverse localities and temperature regimes throughout the world.

(B) The Bryophytes, as a natural reservoir of anticancer compounds, synthesize bioactive secondary metabolites with therapeutic potential. Key bryophyte-derived compounds include Marchantin A, phytol, perrottetin E, prenylated bibenzyls, daucosterol, phenanthrene, perrotettianal A, and lepidozin G. These bioactive molecules, derived primarily from liverworts and mosses, exhibit significant cytotoxic and anticancer activities, underscoring bryophytes as a promising source of novel chemotherapeutic agents.

(C) Schematic representation of anticancer compounds isolated from bryophytes and their diverse mechanisms of action. Key metabolites such as Marchantin A, phytol, perrottetin E, prenylated bibenzyls, daucosterol, phenanthrene, perrotettianal A, and lepidozin G demonstrate multifaceted anticancer potential. Their mechanisms include induction of apoptosis (programmed cell death), cell cycle arrest in cancer cells, inhibition of angiogenesis and tumor progression, suppression of metastasis and invasion, and modulation of signaling pathways involved in cancer proliferation. Together, these compounds highlight bryophytes as a rich reservoir of novel bioactive agents, offering promising leads for future cancer therapeutics.

Full text

Unlocking the medicinal secrets of bryophytes

The bryophytes, though often overlooked worldwide, possess remarkable ethnomedicinal potential. Packed with unique bioactive compounds and molecular treasures, these tiny plants hold immense promise for groundbreaking advances in biotechnology, pharmaceuticals, and medicine (Fig. 1) (Drobnik and Stebel 2021). The Conocephalum conicum stood out as the sole bryophyte species widely recognized for its therapeutic applications until the 19th century. Although the medicinal promise of bryophytes dates to ancient times, their potential remained largely overshadowed by their small size, difficulty of identification, and the absence of striking organs that capture attention compared with other medicinal plants. However, traditional uses of bryophytes reveal a fascinating alignment with modern science, especially in treating skin ailments, infections, and cancer, highlighting their hidden power in natural medicine (Drobnik and Stebel 2021). In China, the Sphagnum teres is prized for treating eye diseases, while Haplocaldium microphyllum is traditionally used to combat urinary tract infections, chest pain, and sore throats. Meanwhile, Rhodobryum giganteum and R. roseum have long been valued for their significant role in treating nerve disorders and supporting cardiovascular health, highlighting the rich medicinal heritage of bryophytes in Chinese herbal medicine. The Polytrichum commune is renowned for its powerful diuretic and analgesic properties. A wide range of bryophyte species, such as Bryum argenteum, Conocephalum conicum, Marchantia polymorpha, Weissia controversa, Climacium dendroides, Funaria hygrometrica, Rhodobryum roseum, Sphagnum species, and Reboulia hemisphaerica, traditionally have been used to treat various diseases (Drobnik and Stebel 2021). Bryophytes boast a diverse spectrum of powerful biological properties, ranging from antioxidant to antibacterial, antifungal, antiviral, and antitumor activities, making them a potential target for groundbreaking pharmaceutical innovations. Given their remarkable medicinal properties, bryophytes are being explored as natural allies in the fight against deadly diseases, such as cancer, one of the most formidable health challenges of the present time.

(A) Occurrence and habitat preferences of major bryophyte groups. Liverworts (Marchantia, Radula, Pellia, Riccia, Lunularia, Porella, and Lepidozia) flourish in cool, moist niches (10 to 25 °C); some grow in humid soils, rooftops, and alpine bogs, thriving at 5 to 20 °C. Mosses (Octoblephrum) grow in warmer, damp fields and rice paddies at 25 to 30 °C. Together, these bryophyte groups exhibit a remarkable ecological spread ranging from urban walls to mountain slopes and peat bogs, highlighting their adaptability to diverse localities and temperature regimes throughout the world.

Bryophyte compounds vs. cancer: inside the cell-killing mechanisms

Cancer remains one of the deadliest diseases globally, with a staggering 19.3 million new cases and nearly 10 million deaths reported in 2020 alone (Ferlay et al. 2021). Although some cancer treatments and drugs are available, their significant side effects and unclear mechanisms of action highlight the urgent need to discover novel, safer, and more effective anti-cancer compounds. Plants have long been recognized as valuable sources of anti-cancer compounds with minimal toxicity. However, the search for novel plant-based therapies is more crucial than ever. Among these, bryophytes—an underexplored group of plants—hold tremendous untapped potential for producing powerful anti-cancer agents, making them a promising frontier in cancer research today (Fig. 2).

(B) The Bryophytes, as a natural reservoir of anticancer compounds, synthesize bioactive secondary metabolites with therapeutic potential. Key bryophyte-derived compounds include Marchantin A, phytol, perrottetin E, prenylated bibenzyls, daucosterol, phenanthrene, perrotettianal A, and lepidozin G. These bioactive molecules, derived primarily from liverworts and mosses, exhibit significant cytotoxic and anticancer activities, underscoring bryophytes as a promising source of novel chemotherapeutic agents.

Recent studies have confirmed that bryophytes are a potent reservoir of bioactive compounds capable of suppressing cancer cell growth through multiple, highly effective mechanisms (Fig. 3). Marchantin A, a macrocyclic bisbibenzyl compound derived from the liverwort Marchantia polymorpha, has garnered attention for its remarkable cytotoxic potency against a range of cancer cell lines (Sen et al. 2023). Exhibiting strong anticancer potential, Marchantin A markedly reduces cell viability in breast cancer cell lines (T47D, MCF7) and mammary epithelial cells (A256), with its most pronounced cytotoxic impact observed in A256 cells. Additionally, Marchantin A has demonstrated significant cytotoxicity against KB cells (Sen et al. 2023). Marchantin A exerts its anticancer effects by triggering apoptosis, marked by elevated levels of activated caspases and poly (ADP-ribose) polymerase (PARP), alongside a reduction in the pro-apoptotic protein Bid levels. In addition to its pro-apoptotic effects, Marchantin A modulates the cell cycle by enhancing the expression of the cell cycle inhibitors p21 and p27 and suppressing the cell cycle driver's cyclin B1 and cyclin D1 (Huang et al. 2010). Beyond its cytotoxic and cell cycle–modulating effects, Marchantin A also acts as a powerful free radical scavenger, adding an antioxidant dimension to its anticancer potential (Huang et al. 2010). Extending its therapeutic promise, Marchantin A has been evaluated in human skin models, demonstrating activity in both immortalized keratinocytes (HaCaT) and malignant melanoma cells (A375). Interestingly, Marchantin A displayed selective toxicity, sparing normal keratinocytes while effectively targeting melanoma cells. Hence, from these findings, Marchantin A emerges as a promising candidate, showing good efficacy with a low risk of side effects (Huang et al. 2010).

(C) Schematic representation of anticancer compounds isolated from bryophytes and their diverse mechanisms of action. Key metabolites such as Marchantin A, phytol, perrottetin E, prenylated bibenzyls, daucosterol, phenanthrene, perrotettianal A, and lepidozin G demonstrate multifaceted anticancer potential. Their mechanisms include induction of apoptosis (programmed cell death), cell cycle arrest in cancer cells, inhibition of angiogenesis and tumor progression, suppression of metastasis and invasion, and modulation of signaling pathways involved in cancer proliferation. Together, these compounds highlight bryophytes as a rich reservoir of novel bioactive agents, offering promising leads for future cancer therapeutics.

Phytol, another significant bioactive compound, is naturally found in Riccia billardieri. Phytol, a diterpene alcohol essential for vitamin E biosynthesis, along with caryophyllene, has shown significant anti-proliferative effects in colorectal cancer cell lines HT-29 and HCT-116 (Sharma et al. 2023). Phytol's anticancer potential lies in its dual action: suppressing proliferation and inducing apoptosis through upregulation of Bax and downregulation of Bcl-2, thereby inhibiting tumor progression. Beyond its pro-apoptotic effects, phytol disrupts tumor-supporting angiogenesis and modulates crucial pathways, such as PI3K-Akt and NF-κB, to hinder cancer development (Yu et al. 2025). The R. billardieri pronounced effects on CRC cells suggest that bryophytes may serve as a powerful natural resource for developing new colorectal cancer therapies (Sharma et al. 2023).

Perrottetin E, a unique bis(bibenzyl) ether derived from the liverworts Pellia endiviifolia and Radula perrottetii, has emerged as a promising natural compound with notable anticancer potential. This cyclic molecule has shown moderate to strong cytotoxic activity against a range of human cancer cell lines, including HL-60 (acute promyelocytic leukaemia), U-937 (acute monocytic leukaemia), K-562 (chronic myelogenous leukaemia), as well as nasopharyngeal carcinoma (KB), glioblastoma, and other leukemia cells, highlighting its potential as a valuable lead in cancer therapy research (Ivković et al. 2021). Perrottetin E exerts its potent anticancer effects by triggering cell death through both intrinsic and extrinsic apoptotic pathways. Studies suggest that its mechanism of action involves a multifaceted assault on cancer cells: disrupting mitochondrial membrane potential, generating reactive oxygen species, and elevating intracellular calcium (Ca²⁺) levels. These combined cellular disruptions lead to enhanced apoptosis and cytotoxicity, underscoring perrottetin E's potential as a powerful and promising chemotherapeutic agent (Ivković et al. 2021).

Prenylated bibenzyls, distinguished by their bibenzyl core structure, represent a fascinating class of natural compounds predominantly found in liverworts of the Radula genus. Often isolated as racemic mixtures, these unique dimers have shown remarkable cytotoxic potential. Studies reveal that prenylated bibenzyl dimers possess significant inhibitory activity against a range of human cancer cell lines, including PC-3 (prostate cancer), MCF-7 (breast cancer), and lung cancer lines A549 and NCI-H1299 (Zhang et al. 2021a, b). The potent anticancer activity of prenylated bibenzyls stems from their ability to target cancer cells through multiple, synergistic mechanisms. These include the induction of mitochondrial-mediated apoptosis, disruption of the cell cycle, and inhibition of tubulin polymerization—a vital process for cell division. Remarkably, these compounds also impair the survival of cancer stem cells by suppressing key signaling pathways, such as the Akt/GSK3β/β-catenin axis (Zhu et al. 2021). Together, these effects lead to effective cancer cell death and significant inhibition of tumor growth and proliferation, positioning prenylated bibenzyls as promising candidates in the fight against cancer.

Phenanthrene, a polycyclic aromatic hydrocarbon, serves as the structural backbone for perrottetin derivatives isolated from the liverwort Lunularia cruciata, which have demonstrated impressive cytotoxic activity, especially against A549 lung cancer cells (Novakovic et al. 2019). These compounds exert their anticancer effects through a multifaceted mechanism, including the induction of mitochondria-mediated apoptosis, generation of DNA damage, activation of oxidative stress, and disruption of cellular metabolism (He et al. 2022). Certain phenanthrene derivatives, particularly phenanthrene-based tylophorines, amplify anticancer effects by selectively targeting and inhibiting critical signaling pathways such as Akt and NF-κB. This targeted disruption leads to cell cycle arrest and triggers apoptotic cell death, significantly weakening cancer cell survival (Lin et al. 2009). These powerful bioactivities underscore the potential of phenanthrene and its derivatives as promising and innovative candidates in the development of next-generation anticancer therapies.

Daucosterol and friedelin, two bioactive compounds first isolated from the moss Octoblepharum albidum, have demonstrated impressive anticancer activity against PA1 (ovarian cancer), C-33A (cervical cancer), and NCI-H358 (lung cancer) cell lines. Using the sulforhodamine B assay, these compounds exhibited strong cytotoxic effects selectively toward cancer cells, while maintaining low toxicity in normal human mammary epithelial cells. This selective action highlights their potential as effective and safer anticancer agents with minimal impact on healthy tissues (Naidu et al. 2020).

Another noteworthy anticancer compound, perrottetianal A—isolated from Porella viridissima—has demonstrated potent cytotoxic activity against the A2780 ovarian cancer cell line (Métoyer et al. 2021). Similarly, lepidozin G, derived from the liverwort Lepidozia reptans, has also shown promising anticancer potential. Lepidozin G has been shown to induce potent anticancer effects in PC-3 prostate cancer cells by triggering apoptosis, promoting the accumulation of reactive oxygen species, and causing significant mitochondrial dysfunction. These combined actions underscore its potential as a powerful agent in prostate cancer therapy (Zhang et al. 2021a, b).

Collectively, these reports highlight bryophytes as a rich and largely untapped source of potent anticancer compounds. Given the significant side effects associated with many current cancer therapies, there is an urgent need to discover safer, more effective alternatives. Bryophytes, often overlooked in drug discovery, offer immense promise as novel sources of anticancer agents, warranting deeper exploration and research in the quest for next-generation cancer therapeutics.