Typhonium flagelliforme

Typhonium flagelliforme (Rodent Tuber / Keladi Tikus)

1. Identity: Botanical Classification, Names, and Natural Source

Scientific name: Typhonium flagelliforme (G.Lodd.) Blume. The species was first described under the name Arum flagelliforme by George Loddiges in the Botanical Cabinet in 1820, based on material likely from Southeast Asia. It was later transferred to the genus Typhonium by Carl Ludwig Blume in Rumphia in 1837, reflecting advancements in aroid taxonomy that recognized the distinct generic boundaries within Araceae. The NCBI Taxonomy database records the basionym as Arum flagelliforme G.Lodd., 1820, placed within the family Araceae, subfamily Aroideae, tribe Areae.

Typhonium flagelliforme is classified in the kingdom Plantae, phylum Tracheophyta, class Liliopsida, order Alismatales, family Araceae, genus Typhonium. The Royal Botanic Gardens, Kew (Plants of the World Online) recognizes several synonyms, including Typhonium hastiferum Miq., Typhonium incurvatum Blatt. & McCann, Typhonium reinwardtianum de Vriese & Miq., and Typhonium sylvaticum Voigt.

Common Names

• In Malay/Indonesian: Keladi tikus; in Chinese: Tu Ban Xia or Lao Shu Yu.
• The English common name "rodent tuber" emphasizes the rodent-like shape of the underground tuber.
• In Tagalog (Philippines), it is called "gabi ng daga" or "gabi-daga," translating to "rat taro."
• In Indonesia: Keladi tikus; in Chinese: Lao shu yu; in India: Nalenschena major; in Singapore: Birah taecchil.
• In Thailand: sa oy (Surin), ta phit kap yao (Loei), wan dakdae (Yasothon); in Vietnam: bán hạ roi, củ chóc mo dài.
• In Chinese medicine it is also referred to as Bian Yan Li Tou Jian or Shui Banxia.

Natural Distribution and Habitat

Typhonium flagelliforme is native to China (Guangdong, Guangxi, Yunnan), Bangladesh, Bhutan, Cambodia, India, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Sri Lanka, Thailand, New Guinea, and Australia (Queensland, Northern Territory). It is found in disturbed wastelands and damp shady habitats; in shallow water by streams, water fields, and moist meadows, often in ditches and along field margins, less often in wet open forest, from 0 to 350 m above sea level.

Botanical Description

Leaves are produced each year from an underground corm 1.5–2 cm in diameter. The rhizome is short, tuberous, and whitish, 1–2 cm long; leaves are variable, 5 to 25 by 0.5 to 18 cm, and may be linear, lanceolate, elliptic, or hastate. The spathe base is greenish-white and pinkish, 3–3.5 cm long; the limb is narrowly lanceolate, 10–25 cm long, greenish on the outside and purplish-brown to white inside; the appendix is subsessile, 18–20 cm long, deeply ridged and channelled. The fruit is a 1-seeded orange-red berry usually found in the large persistent spathe base.

2. Traditional and Historical Use

Malaysia and Singapore

T. flagelliforme is used in traditional medicine in Peninsular Malaysia and Singapore for treating different types of malignancy, while in Thailand the whole plant is applied as a poultice to abscesses. Traditionally, Typhonium flagelliforme is used to treat cancer in Malaysia; people take it as powder or in combination with milk or different types of other herbal extracts as treatment of different types of cancers. Traditionally, T. flagelliforme is taken with fruit juice or as dry extract with other herbal medicine as an alternative therapy in Malaysia to treat various types of cancer. The flowers of T. flagelliforme have been used to arrest bleeding; the plant is considered an indigenous medicinal plant of Malaysia endowed with curative properties against a variety of illnesses including injuries, oedema, coughs, pulmonary ailments, bleeding, and cancer.

Vietnam, Thailand, and the Broader Region

In Vietnam, the tubers are used to treat cough, asthma, and nausea. In traditional medicine, T. flagelliforme is used to treat cough, headache, chronic stomach pain, and tracheitis; fresh bulbs are used for furuncles and the bites of poisonous insects. T. flagelliforme is used to soothe the stomach, combat nausea and vomiting, and reduce epigastric and abdominal distention; the plant also relieves pain, inflammation, and relaxes spasms, and is used for lymphatic swellings.

Traditional Chinese Medicine

The dried stem tubers of Typhonium flagelliforme from the Araceae family are used as a Chinese medicine known as Shui Banxia. They have been reported to have a strong irritative effect on mucosa, with previous studies indicating that the pure raphides of calcium oxalate contained in the stem tubers are responsible for this irritation. The polar extracts were investigated in vivo and found to ease expectoration; they are also antiasthmatic, anti-inflammatory, analgesic, and sedative.

Traditional Preparations

Typhonium flagelliforme, or "rodent tuber," has been widely used in traditional medicine, particularly in Malaysia, for ailments such as cancer, respiratory disorders, swelling, wounds, and gastric discomfort; it is traditionally consumed as raw tubers, juice, or decoctions and is regarded as a versatile remedy in Southeast Asian ethnomedicine. Ethnobotanically, T. flagelliforme is wild-harvested across Indonesia and Malaysia for local markets, where demand surged in the late 1990s and 2000s due to its incorporation into herbal supplements.

3. Key Phytochemical Constituents and Active Compounds

Overview of Phytochemical Classes

Typhonium flagelliforme (Araceae) is a medicinal herb endowed with curative properties against a variety of illnesses including injuries, oedema, coughs, pulmonary ailments, bleeding, and cancer. Phytochemical screening of ex vitro and in vitro extracts revealed alkaloids, flavonoids, terpenoids, and steroids; alkaloids and flavonoids are the main phytochemical constituents, found in the highest amounts in two- and four-month-old ex vitro plants. The leaves and tuber extracts are known to contain secondary metabolite compounds belonging to the classes of flavonoids, alkaloids, triterpenoids, steroids, saponins, and tannins, which act as antimicrobials.

Flavonoids: Vitexin and Isovitexin

A key focus of updated phytochemical research concerns the flavonoid compounds vitexin and isovitexin. These compounds exhibit a wide range of pharmacological activities, including antioxidant, anti-inflammatory, anti-cancer, reduced immunosuppressive effects by reducing lymphocyte proliferation, antibacterial, improved immune system activities, and gastric ulcer healing. Isovitexin has been shown to possess antioxidant and anti-inflammatory activities, and it shares similar pharmacological effects with vitexin, likely due to its similar chemical structure; its excellent antioxidant capacity creates a favorable opportunity to utilize it in cosmetic formulations. Flavonoids such as isovitexin and vitexin promote apoptosis and inhibit cell proliferation via various signaling pathways; vitexin's action involves downregulation of Bcl-2 and upregulation of caspase-3 and caspase-9, while also inducing autophagy through Hsp90 activation.

Fatty Acids and Lipid-Class Compounds

Other chemical constituents identified in this plant include hexadecanoic acid, oleic acid, linoleic acid, linolenic acid, campesterol, stigmasterol, and β-sitosterol. The hexane extract was evaluated for cytotoxic activity and the partial chemical constituents were identified as methyl esters of hexadecanoic acid, octadecanoic acid, 9-octadecenoic acid, and 9,12-octadecadienoic acid. Several common aliphatic hydrocarbons (dodecane through eicosane) were identified, along with the unique methyl ester of 13-phenyltridecanoic acid, isolated and positively identified using spectroscopic methods. A key bioactive lipid fraction is the linoleic acid-rich dichloromethane fraction DCM/F7. GC-MS revealed that DCM/F7 contains linoleic acid, hexadecanoic acid, and 9-hexadecanoic acid.

Pheophorbides (Chlorophyll Derivatives)

Four pheophorbide-related compounds — pheophorbide-a, pheophorbide-a', pyropheophorbide-a, and methyl pyropheophorbide-a — were identified in the most active fraction D/F19; these constituents exhibited antiproliferative activity against cancer cells, with activity increasing following photoactivation, though the greater antiproliferative activity of D/F19 itself compared to its subfractions suggests synergistic action between the constituents, and the inhibitory effect was apoptotic even in the absence of light.

Sterols

Stigmasterol, a steroid compound, regulates cell death through the PI3K/Akt pathway and modulates cyclin proteins to inhibit proliferation. The raphides of calcium oxalate in the stem tubers of Araceae species including T. flagelliforme contain secondary metabolites including beta-sitosterol, sitosterol palmitate, trigonelline, octadecenoic acid, pedatisectine A, and thymidine.

Phenylpropanoid Glycosides and Cerebrosides

Phenylpropanoid glycosides, sterols, and a cerebroside which has antihepatotoxic activity were reported from the root of this plant.

Ribosome-Inactivating Proteins (RIPs)

The rodent tuber extract contains ribosome-inactivating proteins (RIPs) capable of cutting the DNA or RNA of cancer cells and blocking the growth of cancer cells. RIPs represent a structurally distinct class of compounds separate from the small-molecule phytochemicals and are considered a contributor to the plant's reported anticancer activity.

Calcium Oxalate Raphides

Pure calcium oxalate crystals isolated from the raw rhizome of Typhonium flagelliforme showed strong irritation effects in rabbit-eye models. Due to the presence of calcium oxalate crystals causing toxicity, the plant is avoided as fodder for livestock.

4. Mechanisms of Action

Apoptosis Induction

A 2023 systematic review of preclinical studies found that T. flagelliforme induced apoptosis by halting the cell cycle, activating caspase-3 and caspase-9, cleaving PARP, fragmenting DNA, reducing survivin, decreasing reactive oxygen species (ROS), suppressing COX-2 and HSP70, and inhibiting the NF-κB pathway. When combined with interferon, T. flagelliforme also exerts antiangiogenic effects.

Cytological observations in leukemia-cell studies showed chromatin condensation, cell shrinkage, abnormalities of cristae, membrane blebbing, cytoplasmic extrusions, and formation of apoptotic bodies; DCM/F7 also increased cellular DNA breaks in treated cells.

In breast cancer stem cell (bCSC) research, T. flagelliforme tuber extract (TFTe) was found to induce apoptosis in bCSCs by decreasing survivin expression levels and increasing the levels of caspase-9 and caspase-3.

Cell-Cycle Arrest

In vitro findings demonstrated that methanolic rhizome extract induced apoptosis in different cell lines at low concentrations, and cell cycle arrest at the G2/M phase was observed in SCC-225 (oral squamous cell carcinoma) cells.

Anti-inflammatory Mechanism

All water, alcohol, and ester extracts of T. flagelliforme were found to have effects of relieving cough, eliminating expectoration, antiasthmatic activity, analgesia, anti-inflammation, and sedation in a Chinese pharmacological study. COX-2 suppression is one of the molecular anti-inflammatory mechanisms identified in preclinical models, as noted in the systematic review cited above.

Antioxidant Mechanism

In a study of antibacterial and antioxidant activity, ethyl acetate, n-butanol, and water fractions of leaf extract demonstrated antibacterial activity, and by DPPH free radical scavenging methodology the ethyl acetate fraction was the most active (IC50 = 56.32 ppm) among the fractions tested.

Hepatoprotective Mechanism

Pharmacological studies conducted on rats indicated that the juice extract was able to prevent hepatocarcinogenesis. The cerebroside isolated from the root, noted above, has been specifically characterized as possessing antihepatotoxic activity.

5. Scientific Evidence by Area of Use

5a. Oncology / Anticancer Activity

Overview of the evidence base: The overwhelming majority of evidence for anticancer activity is preclinical (in vitro cell-line studies and rodent in vivo experiments). No completed, published human clinical trials of T. flagelliforme as a standalone anticancer agent were identified in the peer-reviewed literature as of 2023.

A systematic review published in 2023 aimed to assess the potential of Typhonium flagelliforme (referred to in Chinese medicine as Bian Yan Li Tou Jian) as an anticancer agent; seven databases — Scopus, PubMed, Web of Science, ScienceDirect, LILACS, EBSCO Medline, and Mendeley — were searched from their inception to September 8, 2023; peer-reviewed English-language studies conducting in vitro and in vivo investigations were included, while clinical trials and non-original reports were excluded. T. flagelliforme extracts were shown to be effective against leukemic, breast, colorectal, and lung cancers in preclinical models; most studies received "Reliable with Restrictions" quality scores; the plant induced apoptosis by halting the cell cycle, activating caspase-3/-9, cleaving PARP, fragmenting DNA, reducing survivin, decreasing ROS, suppressing COX-2 and HSP70, and inhibiting the NF-κB pathway. The review concluded that although T. flagelliforme shows promising activity against cancer, its efficacy as a standalone anticancer treatment remains uncertain.

In vitro studies — leukemia: A study evaluating the in vitro anti-leukemic activity of the dichloromethane extract/fraction 7 (DCM/F7) from T. flagelliforme tuber on human T4 lymphoblastoid (CEMss) cells fractionated the DCM extract by column chromatography and evaluated fractions for cytotoxicity toward CEMss cells and primary human blood lymphocytes (PBLs); apoptosis was assessed by microscopy and TUNEL assay; GC-MS was used for phytochemical screening; 7 out of 12 fractions showed significant cytotoxicity against CEMss, with fractions DCM/F7, DCM/F11, and DCM/F12 showing exceptional activity with IC50 values of 3, 5, and 6.2 μg/mL, respectively. The overall results indicated that T. flagelliforme possesses a valuable anti-leukemic effect and was able to produce distinctive morphological features of cell death corresponding to apoptosis. CEMss cells were far more sensitive to the cytotoxic action of DCM/F7 compared to PBLs, consistent with earlier work showing that DCM fractions were cytotoxic to NCI-H23 lung cancer cells but not to noncancerous BALB/c 3T3 fibroblasts.

In vitro studies — lung cancer: Several fractions of hexane and dichloromethane extracts were found to inhibit the growth of NCI-H23 non-small cell lung carcinoma cell line significantly (IC50 <15 μg/mL); however, most of these active fractions also inhibited non-tumorigenic BALB/c 3T3 mouse fibroblast cells; fraction 21 of the dichloromethane extract (D/F21) was the exception — it was less cytotoxic to non-tumorigenic cells (IC50 48.6 μg/mL) versus NCI-H23 (IC50 7.5 μg/mL), and GC-MS analysis revealed it contains hexadecanoic acid, 1-hexadecene, phytol, and a phytol derivative; D/F21 was identified as the active cancer-cell-specific fraction.

In vitro studies — breast cancer: A bioactivity-guided study aimed to identify chemical constituents with antiproliferative properties against human cancer cell lines; chromatographic purification was combined with antiproliferative MTT assay on NCI-H23 (lung cancer) and HS578T (breast cancer) cell lines; microscopic observation and TUNEL assay confirmed apoptosis; four pheophorbide-related compounds were identified in the most active fraction. A study investigating cytotoxicity of methanolic leaves extract of T. flagelliforme on MDA-MB-231 breast cancer cells used the MTT assay and found that the extract showed an IC50 of 0.11 mg/mL against MDA-MB-231 cells.

In vitro studies — breast cancer stem cells: Breast cancer stem cells (bCSCs), characterized as CD44+/CD24-/low, develop apoptosis resistance by expressing survivin and suppressing caspase-9 and caspase-3; T. flagelliforme tuber extract (TFTe) was assessed for its ability to induce apoptosis in bCSCs; concentrations of 25, 50.89, and 100 μg/mL of TFTe were used to treat bCSCs for 24 hours. The conclusion was that TFTe can induce apoptosis in bCSCs by decreasing survivin expression levels and increasing the levels of caspase-9 and caspase-3.

In vitro studies — oral cancer: Investigation of the anticancer and anti-inflammatory potential of aqueous, acetone, ethanolic, and methanolic extracts against various cell lines showed that proliferation of T. flagelliforme-treated oral cancer cells was significantly inhibited by the downregulation of NEK-7 expression.

Early in vitro study (first reported activity): An early study (Chan et al., 2001) evaluated the hexane extract of T. flagelliforme for cytotoxic activity against P388 murine leukaemia cells in vitro, showing a weak IC50 of 15 μg/mL; none of the individually identified compounds were known to have cytotoxic behaviour.

Evidence strength: All identified anticancer studies for T. flagelliforme are preclinical (in vitro cell-line assays or rodent models). Despite these promising preclinical findings, robust clinical trials in humans are limited, and the available evidence does not yet conclusively validate its efficacy for specific health conditions.

5b. Respiratory / Antitussive and Antiasthmatic Activity

A pharmacological study demonstrated that all water, alcohol, and ester extracts of T. flagelliforme have effects of relieving cough, eliminating expectoration, antiasthmatic activity, analgesia, anti-inflammation, and sedation in a Chinese pharmacological investigation. A low cytotoxic polar fraction of the plant was found to provide relief in cough and asthma in animal models. This plant has shown promising results as a cough suppressant in animal model research, which may be relevant to various respiratory tract problems. These findings are from animal model and in vitro work; no human clinical trials for respiratory indications have been identified.

5c. Gastroprotective Activity

In an animal study, T. flagelliforme aqueous leaf extract was used to investigate its gastroprotective effect in adult Sprague Dawley rats; rats were orally pre-treated with sterile distilled water (ulcer control), omeprazole 20 mg/kg (reference group), or 250 mg/kg and 500 mg/kg of T. flagelliforme extract one hour before oral administration of absolute ethanol to generate gastric mucosal injury; after an additional hour the rats were sacrificed and ulcer areas were determined; the ulcer control group exhibited severe mucosal injury. This research is rat-model data only; no human gastroprotective trials have been identified.

5d. Hepatoprotective Activity

Pharmacological studies conducted on rats indicated that T. flagelliforme juice extract could prevent hepatocarcinogenesis. Phenylpropanoid glycosides, sterols, and a cerebroside with antihepatotoxic activity have been reported from the root. All hepatoprotective data are from animal or in vitro studies; no human clinical data have been identified.

5e. Antimicrobial and Antioxidant Activity

Antibacterial testing by agar diffusion method and antioxidant testing by DPPH, FTC, and TBA methods showed that the ethyl acetate, n-butanol, and water fractions of T. flagelliforme leaf extract had antibacterial activity against Bacillus subtilis and Pseudomonas aeruginosa, while the n-hexane fraction had no activity against the bacteria tested; the ethyl acetate fraction was the most active antioxidant fraction (IC50 = 56.32 ppm). These findings are in vitro laboratory data; no clinical antimicrobial trials have been identified.

5f. Immunomodulatory Activity

Single extracts of T. flagelliforme tuber exert immunomodulatory activity; combining P. niruri, T. flagelliforme, and P. crocatum can improve lymphocyte proliferation, and the combination has been considered a cellular immunostimulator. Immunomodulatory claims in the literature are based on in vitro lymphocyte proliferation assays and animal studies.

6. Body Systems and Health Areas Associated with T. flagelliforme

Pharmacological studies reveal diverse bioactivities including anticancer, anti-inflammatory, immunomodulatory, antioxidant, antimicrobial, gastroprotective, and hepatoprotective effects, aligning closely with its traditional use in Malaysia for ailments such as cancer, respiratory disorders, swelling, wounds, and gastric discomfort.

• Oncology (hematologic, breast, colorectal, lung, cervical, oral cancers): Preclinical evidence only; no clinical trial data.
• Respiratory system (cough, asthma, expectoration): Animal model and in vitro evidence; traditional use well-documented.
• Gastrointestinal system (gastric ulcer, nausea, abdominal distention): Animal model evidence; traditional use documented.
• Hepatic system (hepatoprotection, anti-hepatocarcinogenesis): Rat model evidence.
• Immune system (immunomodulation, lymphocyte proliferation): In vitro and combination-herbal animal studies.
• Skin / wounds / abscesses: Traditional topical use (poultice) documented across Southeast Asia.
• Pain and inflammation: Animal pharmacological studies; traditional use documented.

7. Dosage Forms and Dosages Reported in Studies

Traditional / Ethnobotanical Preparations

Traditionally consumed as raw tubers, juice, or decoctions. In Malaysia, T. flagelliforme is taken with fruit juice or as a dry extract combined with other herbal medicine as an alternative cancer therapy. The plant is also taken as a powder or in combination with milk.

In Vivo / Preclinical Study Dosages

• Gastroprotective (rat model): In the rat gastroprotective study, rats were orally pre-treated with 250 mg/kg and 500 mg/kg of T. flagelliforme aqueous leaf extract, compared to omeprazole 20 mg/kg as a reference.
• Acute toxicity (mice, herbal combination): In acute toxicity testing conducted per OECD 423, the combination herbal product containing T. flagelliforme was safe up to 5000 mg/kg b.w. in male and female SD rats; in repeated 90-day subchronic testing, doses of 22.5, 45, and 90 mg/kg b.w. per day did not affect clinical signs, body weight, food and water consumption, hematological parameters, clinical chemical parameters, urinalysis, relative organ weights, or gross and histopathological features.
• Acute toxicity (LD50, T. flagelliforme alone): The lethal dose of T. flagelliforme causing 50% of deaths (LD50) was reported as 48.081 g/kg b.w.
• Chinese pharmacological study: The maximum tolerances of T. flagelliforme (TFB) in acute toxicity were reported as 720 g/kg (water extract), 900 g/kg (alcohol extract), and 3240 g/kg (ester extract) in mice.
• In vitro breast cancer stem cell study: The study employed TFTe at concentrations of 25, 50.89, and 100 μg/mL to treat bCSCs for 24 hours.
• In vitro leukemia study (DCM/F7 fraction): DCM fractions and the maximum concentration used in the leukemia study were <30 μg/mL; fractions DCM/F7, DCM/F11, and DCM/F12 exhibited activity with IC50 values of 3, 5, and 6.2 μg/mL, respectively.

No standardized or validated human clinical dosage has been established for any indication. The dosages listed above are exclusively derived from preclinical research.

8. Safety Considerations

Calcium Oxalate Raphide Irritation

Toxicity of Typhonium is not reported extensively in the literature; however, its tuber toxicity presents with airway compromise that resolves over hours, and the symptoms are due to the local effects of calcium oxalate crystals in the tuber. Clinical cases from a related species (Typhonium trilobatum) involved swelling of lips and tongue, drooling of saliva, severe throat pain, and one case of significant upper airway edema and severe respiratory distress requiring emergency endotracheal intubation. Calcium oxalate crystals isolated from the raw rhizome of T. flagelliforme showed strong irritation effects in rabbit-eye models; under the same calcium oxalate content, there was no difference in irritation between suspensions of raw medicinal materials and pure calcium oxalate crystals. The stem tubers of T. flagelliforme have been reported to have a strong irritative effect on mucosa, with previous studies attributing this to the pure raphides of calcium oxalate.

Processing to Reduce Irritation

Previous studies have indicated that pure raphides of calcium oxalate in the stem tubers are responsible for the strong irritation; however, processed products of related species' stem tubers (such as Fabanxia, Qingbanxia, and Jiangbanxia from Pinellia ternata) have been found to have no irritative effects on mucosa. This suggests that appropriate processing methods can mitigate the mucosal irritation associated with raw Araceae tubers.

Formal Toxicology Studies

A formal acute and subchronic oral toxicity evaluation of a herbal formulation containing T. flagelliforme (along with Piper crocatum and Phyllanthus niruri) was conducted; acute toxicity was tested per OECD 423 and subchronic toxicity per OECD 408; the combination product was safe up to 5000 mg/kg b.w. in male and female SD rats. In repeated doses for 90 days at 22.5, 45, and 90 mg/kg b.w. per day, administration did not affect clinical signs, body weight, food and water consumption, hematological, clinical chemical, or urinary parameters, relative organ weights, or histopathological features; analyses suggest that the long-term oral administration for 90 days does not cause subchronic toxicity.

Selectivity Concerns in Anticancer Fractions

In lung cancer research, most active fractions were also found to inhibit the growth of non-tumorigenic BALB/c 3T3 mouse fibroblast cells, raising selectivity concerns. Only fraction D/F21 showed meaningful selectivity between cancer and non-cancer cells in that study.

Overcollection and Sustainability

Southeast Asia, particularly Indonesia and Malaysia, has experienced localized pressures from overcollection for traditional medicinal purposes; high demand for tubers may contribute to overcollection in some areas, compounded by habitat degradation from agricultural expansion.

References

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• NCBI Taxonomy Browser — Typhonium flagelliforme (Taxonomy ID: 458697)
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