IngredientsCephalotaxus sinensis (Rehder & E.H. Wilson) H.L. Li is a major species found in China and is rich in resources. The species belongs to the genus Cephalotaxus, the sole representative of the family Cephalotaxaceae, which is widespread in Southern and Eastern Asia and consists of about 12 species and varieties. The plant is commonly known as Chinese plum yew. In Chinese ethnomedicine, the genus is referred to as Sanjianshan. Cephalotaxus sinensis (Rehd. et Wile) Li., which belongs to the Cephalotaxaceae family, is an endemic species that is widely distributed in China.
Among the approximately 12 species and varieties in the genus, only six species and four varieties are native to China, scattered in Sichuan, Shaanxi, Yunnan, Guangxi, Hainan, and Taiwan provinces. The species has also been encountered in northeastern Himalayan regions; studies of biochemical profiles and biological activity have included C. sinensis alongside other Cephalotaxus species collected in that region.
Cephalotaxus is the only genus of the Cephalotaxaceae family, and its natural resources are declining due to habitat fragmentation, excessive exploitation and destruction.
Cephalotaxus sinensis is a slow-growing, coniferous, evergreen tree or shrub. Cephalotaxus (plum yew) is a slow-growing coniferous tree from the Cephalotaxaceae family that produces over 70 structurally diverse Cephalotaxus alkaloids, with the most prominent being cephalotaxine (CET)—the core structure of Cephalotaxus alkaloids. In research, the plant material most frequently studied consists of the twigs and leaves (needles), seeds, and bark. The main ingredients of C. sinensis are alkaloids, although other ingredients including biflavonoids, flavonoids, diterpenes and lactones have also been isolated.
In pharmaceutical and scientific contexts, C. sinensis serves primarily as a natural source for extraction and isolation of bioactive secondary metabolites. Traditional preparations include decoctions and folk herbal formulations, while modern research utilizes alcohol and organic solvent extracts for phytochemical investigations. Stem and leaf extracts of selected accessions have been biochemically characterized using HPLC/LC–MS.
Cephalotaxus sinensis, a major species found in China and rich in resources, is used as a traditional folk medicine in China to treat inflammation, dyspepsia, ascariasis, and cough. In many areas of China, folk herbal doctors traditionally use Cephalotaxus plants to treat innominate swollen poison, many of which are cancer.
In many areas of China, folk herbal doctors traditionally use Cephalotaxus plants to treat innominate swollen poison, many of which are cancer. Not only among Han people, but also among minority ethnic groups, Cephalotaxus is used to treat various diseases, e.g., cough, internal bleeding and cancer in Miao medicine, bruises, rheumatism and pain in Yao medicine, and ascariasis, hookworm disease, and scrofula in She medicine.
Four Cephalotaxus species are listed in the official medicinal book in China. They are used as ethnomedicines by many ethnic groups such as Miao, Yao, Dong, She, and Han. Classic medicinal books, folk medicine books, herbal manuals and ethnomedicinal publications have been reviewed for the genus Cephalotaxus (Sanjianshan in Chinese).
Some species have a long history of medicinal use in Chinese folk medicine, which was considered as attributed to the anti-cancer alkaloids, such as harringtonine and homoharringtonine. HHT and related compound esters of cephalotaxine were described first in 1970 and were the subject of intensive research efforts by Chinese investigators to clarify their role as anticancer and antileukemic agents from the 1970s until the present.
Homoharringtonine (HHT) is a compound that was first extracted from Cephalotaxus plants by Chinese researchers in the 1970s; it has been widely used in the treatment of hematological diseases in China for more than 40 years. The first clinical studies using HHT were performed in China. In 1976, a study on treating leukemia with HHT showed promising results in 25 patients with AML, with a complete response (CR) in 24% and a partial response (PR) in 64%.
Homoharringtonine-omacetaxine probably holds the dubious record for the longest time of development of an anticancer agent until FDA approval, almost more than 40 years. Traditional use thus directly inspired decades of modern pharmaceutical investigation.
Over the past decades, scientists have obtained diverse and attractive secondary metabolites from the genus Cephalotaxus, including alkaloids, terpenoids, flavonoids, and phenylpropanoids. Notably, alkaloids, especially cephalotaxine-type alkaloids, have attracted considerable attention from medicinal chemists and pharmacologists owing to their potent antitumor activity and their unique pentacyclic ring structure with a side chain bearing an oxygen-containing chiral carbon center.
The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center.
Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). More than 70 compounds have been identified and characterized across the genus. In a 2023 study specifically on C. sinensis, twelve new Cephalotaxus alkaloids and nine known analogues were isolated and identified from the twigs and leaves of Cephalotaxus sinensis, and the structures of the new compounds were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis.
Cephalotane diterpenoids/norditerpenoids (CTDNs), exclusive to the Cephalotaxus genus, are another intriguing class of natural products characterized by a highly rigid backbone, multiple continuous chiral centers, and usually one bridging lactone unit (E-ring). Previous phytochemical investigations have led to the isolation of 73 cephalotane-type diterpenoids from the Cephalotaxus genus, which were classified into five structural types, including Cephalotaxus troponoids (C19) and cephalotane-type diterpenoids (C20).
Specifically from C. sinensis, a landmark 2017 study published in the Journal of Natural Products reported: ten new cephalotane-type diterpenoids, cephanolides A–J (1–10), and two known analogues were isolated and characterized from Cephalotaxus sinensis. Compounds 1–3 represent the first examples of A-ring-contracted cephalotane-type dinorditerpenoids, and compound 4 is an A-ring-contracted norditerpenoid. Compounds 11 and 12 showed significant cytotoxicities against a panel of tumor cell lines (A549, KB, HL-60, and HT-29) with IC50 values ranging from 0.464 to 6.093 μM.
In a 2024 investigation combining C. fortunei var. alpina and C. sinensis, six undescribed cephalotane diterpenoids were isolated. Ceforloid A possesses a new norditerpenoid skeleton incorporating an atypical acetophenone moiety. Ceforloids D and E incorporate a rare 12,13-p-hydroxybenzylidene acetal motif, while ceforloids B and F exhibited mild immunosuppressive activity.
Another dedicated investigation of C. sinensis isolated polycyclic norditerpenoids: four polycyclic norditerpenoids, cephalotanins A–D (1–4) representing three unprecedented carbon skeletons with highly rigid ring systems, were isolated from Cephalotaxus sinensis. Compounds 1 and 2 are new skeletal norditerpenoid trilactones, while 3 and 4 are two norditerpenoids featuring different new carbon skeletons. Compound 1 exhibited good NF-κB inhibition with an IC50 value of 4.12 ± 0.61 μM.
The species has also yielded cephasinenoside A, a new cephalotane diterpenoid glucoside from Cephalotaxus sinensis, as reported in a 2019 study.
The main ingredients of C. sinensis are alkaloids, although other ingredients including biflavonoids, flavonoids, diterpenes and lactones have also been isolated. The alkaloids isolated from Cephalotaxus have anticancer activity, and biflavonoids and lactones from Cephalotaxus were found to have cytotoxic activity.
Results have demonstrated the presence of several medicinally important chemicals in C. sinensis, like harringtonine, rutin, caffeic acid, gallic acid, and a few other biologically active compounds. A 2023 study employed molecular networking for the discovery of biflavonoid alkaloids specifically from C. sinensis.
Diterpenoids, sesquiterpenoids, flavonoids, lignans, phenolics, and other components are also identified and isolated in various Cephalotaxus species. For C. sinensis specifically: in the past decades, many new alkaloids have been isolated and identified from the species. In addition, it is also rich in various valuable compounds, such as terpenoids, lactones, and lignans.
Various compounds have been discovered from Cephalotaxus species, including alkaloids, essential oils, lignans, phenylpropanoids, terpenoids, and flavonoids.
The best-characterized mechanism attributable to constituents of C. sinensis and the broader Cephalotaxus genus relates to the action of homoharringtonine (HHT) and its semisynthetic derivative omacetaxine mepesuccinate. Homoharringtonine has been found to exert inhibitory effects on protein synthesis, which is believed to be the mechanism behind its antineoplastic properties.
HHT acts by inhibiting aminoacyl-tRNA binding to the ribosomal acceptor site, thus preventing peptide bond formation. Omacetaxine mepesuccinate is distinct because it functions as a protein translation inhibitor, disrupting protein synthesis in leukemia cells, a mechanism different from typical tyrosine kinase inhibitors.
Omacetaxine mepesuccinate inhibits protein translation through prevention of the initial elongation step of protein synthesis, and its use benefits CML patients possessing the BCR-ABL oncogene. Omacetaxine has a novel mechanism of action—inhibition of protein synthesis—which does not overlap with kinase inhibition.
Omacetaxine mepesuccinate induces apoptosis in cell lines by inhibiting protein synthesis. It acts by inhibiting aminoacyl-tRNA binding to the ribosomal acceptor site, thus preventing peptide bond formation. Other studies indicate it significantly downregulates myeloid cell leukemia-1 protein (MCL-1), an important anti-apoptotic regulator in AML, which is part of the BCL-2 superfamily.
Homoharringtonine exerts its anti-tumoral and anti-angiogenic activity through inhibition of protein synthesis and the promotion of apoptosis.
Beyond alkaloids, diterpenoids isolated specifically from C. sinensis have shown mechanistic activity through inflammation-related pathways. Compound 1 (cephalotanin A) exhibited good NF-κB inhibition with an IC50 value of 4.12 ± 0.61 μM. NF-κB signaling is a central regulator of inflammation and cancer cell survival, suggesting additional mechanistic relevance of non-alkaloid constituents.
Studies confirmed that Cephalotaxus sinensis has excellent activities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) both indoors and outdoors; its control of TMV is comparable to that of a commercialized antiviral agent (VA; active ingredient = a mixture of moroxydine hydrochloride and copper acetate).
The most extensively studied clinical application of Cephalotaxus-derived HHT concerns the treatment of CML. The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by the European Medicine Agency and by the US Food and Drug Administration in 2012.
Omacetaxine mepesuccinate is a semisynthetic purified HHT compound (99.7% purity) used in recent studies in CML, and approved by the FDA in October 2012 for the treatment of CML in chronic or accelerated phase after failure of 2 or more tyrosine kinase inhibitors (TKIs).
A phase II trial specifically in CML patients with the BCR-ABL T315I mutation who had failed imatinib showed that hematologic responses were observed in 77% of subjects and the duration of response was 9.1 months. A major cytogenetic response was seen in 23% of subjects. These study results led to FDA approval of omacetaxine mepesuccinate for the treatment of CML in October 2012.
In the phase II open-label registration trial, among 46 CML-CP patients who had all received imatinib plus dasatinib and/or nilotinib, 67% achieved or maintained a hematologic response for a median of 7 months. Twenty-two percent achieved major cytogenetic response (4% complete cytogenetic response) and median PFS was 7 months. Grade 3/4 thrombocytopenia, neutropenia, and anemia occurred in 54%, 48%, and 33%, respectively.
A study of HHT combined with low-dose cytarabine (ara-C) in 105 patients with Philadelphia chromosome-positive CML found that the rate of complete hematologic response during the chronic phase was 72%. Additionally, in a study involving 90 patients with Philadelphia chromosome-positive early chronic phase CML, a triple therapy regimen consisting of interferon-alpha, cytarabine, and HHT resulted in a complete hematological remission rate of 94%, with 74% of patients achieving cytogenetic remission.
Evidence strength: Strong, with multiple phase II clinical trials and FDA-approval supporting efficacy of HHT-derived omacetaxine in CML. However, as noted, omacetaxine approval in the US has been discontinued (August 2024) and is no longer recommended for treatment of CML as of NCCN CML guidance 3.2025. The historical clinical evidence base remains robust for its mechanistic and scientific significance.
Although HHT is part of the standard AML therapy in China, the FDA approval of omacetaxine for the narrow indication of CML in chronic or accelerated phases after failure of 2 or more TKI therapies has salvaged this drug from oblivion.
A 2021 meta-analysis on HHT in AML searched PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure, and Wanfang data until October 31, 2020. A total of 37 articles (2,846 patients) fitting the criterion were included. The pooled overall response rate for patients treated with HHT was 82% (CI, 77.9%–85.6%; I² = 73.5%), and the complete response rate was 63.4% (CI, 58.8%–68%; I² = 67.3%). The study showed that patients treated with HHT have more overall response and complete response benefits and less cardiotoxicity and relapse rate.
An earlier 2014 meta-analysis of 21 Chinese studies (n = 1,310 patients) found: overall, the random-effects model showed a CR rate of 65.2%. In studies in which HHT-containing regimens were compared to regimens without HHT, the CR rates were 69.1% in randomized trials and 62.8% in retrospective studies. Higher overall CR rates for HHT-containing regimens in AML treatment in the Chinese studies suggest that HHT could be an active agent in the management of AML. Additional clinical trials are warranted to evaluate the efficacy of HHT in AML treatment.
A meta-analysis of the HAG regimen (homoharringtonine + cytarabine + G-CSF) including 2,314 patients (AML, n = 1,754; MDS, n = 560) found: the CR rate of AML patients (53%) was significantly higher than that of MDS/transformed-AML patients (45%; P = 0.007). The CR rate of patients with newly diagnosed AML (62%) was significantly higher than in patients with relapsed/refractory AML (50%; P = 0.001).
In a single-institution pediatric AML study, patients were treated with a regimen including HHT 3.5 mg/m² per day for 9 days for 6–8 cycles after induction and consolidation with cytarabine plus daunorubicin (DA). One hundred and seventy-one eligible patients, with a median age of 7.58 years, were enrolled. Complete response was obtained in 140/171 (81.9%) cases within 60 days (2 cycles) after DA induction. The 5-year event-free survival was 52.75%.
Evidence strength: Multiple meta-analyses and clinical trials from China support HHT's efficacy in AML combination regimens. Most evidence is from single-arm or retrospective studies; high between-study heterogeneity (I² values often exceeding 60%) limits definitive conclusions. Randomized controlled trial data are limited outside of China.
Phase I studies including a small number of patients (25 patients in one study) have shown benefit in treating myelodysplastic syndrome (MDS). In the HAG regimen meta-analysis, a meta-analysis of 2,314 patients, of whom 560 had MDS, found a CR rate of 45% for MDS/transformed-AML patients, significantly lower than for primary AML (P = 0.007).
Evidence strength: Preliminary; largely from phase I data and subgroup analyses within larger AML studies. No phase III data are available specific to MDS.
Research confirmed that Cephalotaxus sinensis has excellent activities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) both indoors and outdoors. Biflavonoids and lactones from Cephalotaxus were found to have cytotoxic activity. Compounds from Cephalotaxus show antiviral activity, though published research to date concerns primarily plant viruses and in vitro models.
Evidence strength: Preclinical only; no human or mammalian clinical trials on antiviral application from C. sinensis are available in the indexed literature.
Cephalotaxus extracts and compounds showed anti-inflammatory and antioxidant activities, immunomodulatory activity, antimicrobial activity and nematotoxicity, antihyperglycemic effect, and bone effect. From C. sinensis specifically, cephalotanin A demonstrated NF-κB inhibitory activity with an IC50 of 4.12 μM in cell-based assays. Cephalotane diterpenoids from Cephalotaxus have reportedly exhibited anti-inflammatory activities.
Evidence strength: Preclinical and in vitro only. No clinical trials in human inflammatory conditions are reported.
Alkaloids 6, 7, 11, 16, 18 and 19 isolated from C. sinensis exhibited broad and potent cytotoxicities against five human cancer cell lines, with IC50 values ranging from 0.053 to 10.720 μM, highlighting these compounds as promising leads for the development of new antitumor agents.
Alkaloids such as HHT, terpenoids, and other compounds have anticancer activities against multiple types of human cancer. Cephalotane diterpenoids as a major class of compounds in the Cephalotaxus genus have been attracting increasing attention, especially in recent years, due to their previously undescribed structures and significant anticancer, antimalarial, antiviral, anti-inflammatory and plant growth inhibitory activities.
Evidence strength: Predominantly in vitro (cell line-based) with some in vivo animal model data for HHT; human clinical evidence for cytotoxic activities of non-HHT C. sinensis compounds is absent from the current literature.
Cephalotaxus extracts and compounds have been shown to exhibit antihyperglycemic effect in preclinical models. No clinical studies in diabetic patients involving C. sinensis extracts or constituents have been identified in the indexed literature.
Evidence strength: Preclinical only.
As a dietary supplement or crude herbal material, no standardized human dosage for Cephalotaxus sinensis as a whole plant or extract has been established in peer-reviewed clinical literature. The dosage data available relates exclusively to isolated HHT or its semisynthetic derivative omacetaxine, studied as pharmaceutical agents in clinical trials.
On October 26, 2012, the FDA granted accelerated approval to omacetaxine mepesuccinate for subcutaneous use for the treatment of adult patients with chronic- or accelerated-phase CML, with resistance and/or intolerance to two or more tyrosine kinase inhibitors.
Several drug delivery systems have been developed to address the distinctive characteristics of HHT in terms of low solubility and to improve solubilization, stabilization, and targetability to optimize pharmacological activities. A range of drug delivery systems, including nanoparticles, polymeric encapsulation, and liposomes, have been employed for HHT delivery, improving its solubilization, stability, pharmacokinetics, and bioavailability, with targeted delivery to tumors realized.
During clinical trial use, HHT often caused notably cardiovascular disturbances if given rapidly by intravenous infusion. Myelosuppression is the common complication in HHT-based chemotherapy.
The most common (≥20%) adverse reactions of any grade in omacetaxine-enrolled patients included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, and infection. In the pediatric AML study, severe myelosuppression was seen in all patients, with an average minimum WBC count of 686/μl.
Hypotension was generally mild with daily dose levels of 3–4.5 mg/m²/day and required no specific treatment besides IV fluid supplements in some patients. However, hypotension became increasingly severe at higher dose levels and resulted in cardiovascular collapse in four of 16 patients treated at dose levels of 5–6 mg/m²/day.
Serious cardiovascular complications were noted in 30% of patients in early studies. Lower doses and longer exposure schedules of HHT 2.5 to 3 mg/m² daily for 14 days eliminated the cardiovascular complications.
In patients receiving subcutaneous HHT, particularly those who are resistant to imatinib, the tolerance is generally good. However, adverse reactions such as bone marrow suppression, hypotension, mild gastrointestinal toxicity, headaches, and cardiovascular events still occur.
Gastrointestinal toxic effects of nausea, vomiting, and diarrhea were observed in approximately two-thirds of patients in Phase I studies, but these side effects were generally mild and self-limited. Drug-related fever and alopecia were also observed in some patients.
In CML combination studies, toxicities were acceptable, mostly related to moderate diarrhea (3%), headaches (3%), cardiovascular events (3%), and myelosuppression-associated complications (3% to 14%).
Although HHT has anti-growth activity in vitro and praiseworthy achievement in acute and chronic myeloid leukemia treatment, the drug shows no beneficial effect in lymphocytic leukemia and solid tumors. The underlying mechanism for the discrepancy of efficacy remains unknown.
In patients with AML treated with HHT, the rate of cardiac toxicity was reduced versus patients not treated with regimens that included HHT (OR, 0.60; CI, 0.37–0.99; I² = 34.1%; P = 0.046). This finding suggests that HHT-containing regimens may offer a cardiac safety advantage compared to certain anthracycline-based alternatives.
Following the HHT-including regimen in the pediatric AML study, one patient suffered severe pancreatitis, and a second patient with a history of congenital hepatitis B suffered liver failure. These represent rare but serious events observed in clinical settings.
Cephalotaxus's natural resources are declining due to habitat fragmentation, excessive exploitation and destruction. This has driven both semi-synthetic production of HHT from cephalotaxine and biosynthetic research programs aimed at sustainable supply.
Health conditions that Cephalotaxus sinensis may help support.
Body systems that Cephalotaxus sinensis may help support.
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