-
European Journal of Medicinal Chemistry Jul 2018To improve podophyllotoxin's cytotoxicity and selective effect, twenty-two podophyllotoxin derivatives had been designed and synthesized. The cytotoxicity of these...
To improve podophyllotoxin's cytotoxicity and selective effect, twenty-two podophyllotoxin derivatives had been designed and synthesized. The cytotoxicity of these compounds was evaluated on A549, MCF-7, HepG2 and L-02 cell lines. As a result, most of the compounds were more potent than the positive drugs Etoposide (VP-16) and Doxorubicin which were widely used in clinical for antitumor. There were no magnitude differences about these de-protected (without Boc group) podophyllotoxin amino acid derivatives' cytotoxicity between three tumor cell lines and normal hepatic L-02 cells. Interestingly, some protected (with Boc group) amino acid derivatives and some ligustrazine derivatives showed high selectivity, especially the compound 2 (sarcosine derivative with Boc group). It exhibited highly selectivity both on the cancer cells and the normal cells. The IC of compound 2 was 9.5 ± 0.03 nM, 132.6 ± 24.1 nM, 96.4 ± 1.3 nM and 160.2 ± 4.7 nM against A549, MCF-7, HepG2 and L-02 cells, respectively. The SI (IC/IC) value of compound 2, Doxorubicin and Etoposide was 16.9, 0.2 and 0.5, respectively. Meanwhile, SI (IC/IC) value and SI (IC/IC) value of compound 2 were 14.0 and 10.1, respectively. In summary, compound 2 showed high selectivity especially on A549 cells. Further research on cell apoptosis indicated that compound 2 could induce apoptosis of A549 cells through nuclei fragmentation and had lower toxicity to normal hepatic L-02 cells. The detection of apoptosis and cell cycle analysis indicated that compound 2 induced A549 cells apoptosis and prevented A549 cells transition from S to G phase while there were no obvious changes on L-02 cells. Moreover, the structure-activity relationships of these derivatives were briefly discussed.
Topics: Antineoplastic Agents; Cell Cycle; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Structure; Podophyllotoxin; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 29886322
DOI: 10.1016/j.ejmech.2018.05.052 -
Natural Product Reports Mar 2021Covering: up to 2020As a main bioactive component of the Chinese, Indian, and American Podophyllum species, the herbal medicine, podophyllotoxin (PTOX) exhibits broad... (Review)
Review
Covering: up to 2020As a main bioactive component of the Chinese, Indian, and American Podophyllum species, the herbal medicine, podophyllotoxin (PTOX) exhibits broad spectrum pharmacological activity, such as superior antitumor activity and against multiple viruses. PTOX derivatives (PTOXs) could arrest the cell cycle, block the transitorily generated DNA/RNA breaks, and blunt the growth-stimulation by targeting topoisomerase II, tubulin, or insulin-like growth factor 1 receptor. Since 1983, etoposide (VP-16) is being used in frontline cancer therapy against various cancer types, such as small cell lung cancer and testicular cancer. Surprisingly, VP-16 (ClinicalTrials NTC04356690) was also redeveloped to treat the cytokine storm in coronavirus disease 2019 (COVID-19) in phase II in April 2020. The treatment aims at dampening the cytokine storm and is based on etoposide in the case of central nervous system. However, the initial version of PTOX was far from perfect. Almost all podophyllotoxin derivatives, including the FDA-approved drugs VP-16 and teniposide, were seriously limited in clinical therapy due to systemic toxicity, drug resistance, and low bioavailability. To meet this challenge, scientists have devoted continuous efforts to discover new candidate drugs and have developed drug strategies. This review focuses on the current clinical treatment of PTOXs and the prospective analysis for improving druggability in the rational design of new generation PTOX-derived drugs.
Topics: Antineoplastic Agents; Drug Design; Humans; Neoplasms; Podophyllotoxin
PubMed: 32895676
DOI: 10.1039/d0np00041h -
The Cochrane Database of Systematic... Nov 201430% of people with anogenital warts (AGW) have spontaneous regression of lesions but there is no way to determine whether a specific lesion will remain. There are a wide... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
30% of people with anogenital warts (AGW) have spontaneous regression of lesions but there is no way to determine whether a specific lesion will remain. There are a wide range of options available for treating people with AGW and selection is based on clinician's experience, patient preferences and adverse effects. The imiquimod could offer the advantages of patient-applied therapies without incurring the limitations of provider-administered treatments.
OBJECTIVES
To assess the effectiveness and safety of imiquimod for the treatment of AGW in non-immunocompromised adults.
SEARCH METHODS
We searched the Cochrane Sexually Transmitted Infections Group Specialized Register (15 April 2014), CENTRAL (1991 to 15 April 2014), MEDLINE (1946 to 15 April 2014), EMBASE (1947 to 15 April 2014), LILACS (1982 to 15 April 2014), World Health Organization International Clinical Trials Registry (ICTRP) (15 April 2014), ClinicalTrials.gov (15 April 2014), Web of Science (2001 to 15 April 2014) and OpenGrey (15 April 2014). We also handsearched conference proceedings, contacted trial authors and reviewed the reference lists of retrieved studies.
SELECTION CRITERIA
Randomized controlled trials (RCTs) comparing the use of imiquimod with placebo, any other patient-applied or any other provider-administered treatment (excluding interferon and 5-fluorouracil which are assessed in other Cochrane Reviews) for the treatment of AGW in non-immunocompromised adults.
DATA COLLECTION AND ANALYSIS
Three review authors independently assessed trials for inclusion, extracted data and assessed risk of bias. We resolved any disagreements through consensus. The quality of the evidence was assessed using the GRADE approach.
MAIN RESULTS
Ten RCTs (1734 participants) met our inclusion criteria of which six were funded by industry. We judged the risk of bias of the included trials as high. Six trials (1294 participants) compared the use of imiquimod versus placebo. There was very low quality evidence that imiquimod was superior to placebo in achieving complete and partial regression (RR 4.03, 95% CI 2.03 to 7.99; RR 2.56, 95% CI 2.05 to 3.20, respectively). When compared with placebo, the effects of imiquimod on recurrence (RR 2.76, 95% CI 0.70 to 10.91), appearance of new warts (RR 0.76, 95% CI 0.58 to 1.00) and frequency of systemic adverse reactions (RR 0.91, 95% CI 0.63 to 1.32) were imprecise. We downgraded the quality of evidence to low or very low. There was low quality evidence that imiquimod led to more local adverse reactions (RR 1.73, 95% CI 1.18 to 2.53) and pain (RR 11.84, 95% CI 3.36 to 41.63).Two trials (105 participants) compared the use of imiquimod versus any other patient-applied treatment (podophyllotoxin and podophyllin). The estimated effects of imiquimod on complete regression (RR 1.09, 95% CI 0.80 to 1.48), partial regression (RR 0.77, 95% CI 0.40 to 1.47), recurrence (RR 0.49, 95% CI 0.21 to 1.11) or the presence of local adverse reactions (RR 1.24, 95% CI 1.00 to 1.54) were imprecise (very low quality evidence). There was low quality evidence that systemic adverse reactions were less frequent with imiquimod (RR 0.30, 95% CI 0.09 to 0.98).Finally, two trials (335 participants) compared imiquimod with any other provider-administered treatment (ablative methods and cryotherapy). There was very low quality of evidence that imiquimod did not have a lower frequency of complete regression (RR 0.84, 95% CI 0.56 to 1.28). There was very low quality evidence that imiquimod led to a lower rate of recurrence during six-month follow-up (RR 0.24, 95% CI 0.10 to 0.56) but this did not translate in to a lower recurrence from six to 12 months (RR 0.71, 95% CI 0.40 to 1.25; very low quality evidence). There was very low quality evidence that imiquimod was associated with less pain (RR 0.30, 95% CI 0.17 to 0.54) and fewer local reactions (RR 0.55, 95% CI 0.40 to 0.74).
AUTHORS' CONCLUSIONS
The benefits and harms of imiquimod compared with placebo should be regarded with caution due to the risk of bias, imprecision and inconsistency for many of the outcomes we assessed in this Cochrane Review. The evidence for many of the outcomes that show imiquimod and patient-applied treatment (podophyllotoxin or podophyllin) confer similar benefits but fewer systematic reactions with the Imiquimod, is of low or very low quality. The quality of evidence for the outcomes assessing imiquimod and other provider-administered treatment were of very low quality.
Topics: Adult; Aminoquinolines; Anus Diseases; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Imiquimod; Immunocompetence; Interferon Inducers; Keratolytic Agents; Male; Podophyllin; Podophyllotoxin; Randomized Controlled Trials as Topic; Recurrence; Self Administration; Warts
PubMed: 25362229
DOI: 10.1002/14651858.CD010389.pub2 -
Biomedicine & Pharmacotherapy =... Feb 2023The use of plant secondary metabolites has gained considerable attention among clinicians in the prevention and treatment of cancer. A secondary metabolite isolated... (Review)
Review
The use of plant secondary metabolites has gained considerable attention among clinicians in the prevention and treatment of cancer. A secondary metabolite isolated mainly from the roots and rhizomes of Podophyllum species (Berberidaceae) is aryltetralin lignan - podophyllotoxin (PTOX). The purpose of this review is to discuss the therapeutic properties of PTOX as an important anticancer compound of natural origin. The relevant information regarding the antitumor mechanisms of podophyllotoxin and its derivatives were collected and analyzed from scientific databases. The results of the analysis showed PTOX exhibits potent cytotoxic activity; however, it cannot be used in its pure form due to its toxicity and generation of many side effects. Therefore, it practically remains clinically unusable. Currently, high effort is focused on attempts to synthesize analogs of PTOX that have better properties for therapeutic use e.g. etoposide (VP-16), teniposide, etopophos. PTOX derivatives are used as anticancer drugs which are showing additional immunosuppressive, antiviral, antioxidant, hypolipemic, and anti-inflammatory effects. In this review, attention is paid to the high potential of the usefulness of in vitro cultures of P. peltatum which can be a valuable source of lignans, including PTOX. In conclusion, the preclinical pharmacological studies in vitro and in vivo confirm the anticancer and chemotherapeutic potential of PTOX and its derivatives. In the future, clinical studies on human subjects are needed to certify the antitumor effects and the anticancer mechanisms to be certified and analyzed in more detail and to validate the experimental pharmacological preclinical studies.
Topics: Humans; Podophyllotoxin; Antineoplastic Agents; Lignans; Antiviral Agents; Neoplasms
PubMed: 36586242
DOI: 10.1016/j.biopha.2022.114145 -
Xenobiotica; the Fate of Foreign... Sep 2021Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD and...
Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD and .Mouse and human liver microsomes were employed to identify POD metabolites and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All incubation mixtures and bile samples from mice treated with POD were analysed with ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry.A total of 38metabolites, including six phase-I metabolites and 32 phase-II metabolites, of POD were identified from bile and faeces samples after oral administration, and their structures were elucidated through interpreting MS/MS fragmentation patterns.Nine metabolites, including two phase-I metabolites, five glucuronide conjugates, and two GSH conjugates were detected in both human and mouse liver microsome incubation systems and the generation of all metabolites were NADPH-dependent. The main phase-I enzymes involved in metabolism of POD include CYP2C9, CYP2C19, CYP3A4, and CYP3A5.POD administration to mice caused hepatic and intestinal toxicity, and the cellular damage was exacerbated when 1-aminobenzotriazole, a broad-spectrum inhibitor of CYPs, was administered with POD, indicating that POD, but not its metabolites, induced hepatic and intestinal toxicities.This study elucidated the metabolic map and provides important reference basis for the safety evaluation and rational for the clinical application of POD.
Topics: Animals; Antiviral Agents; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Mice; Microsomes, Liver; Podophyllotoxin; Tandem Mass Spectrometry
PubMed: 34319859
DOI: 10.1080/00498254.2021.1961920 -
Supportive Care in Cancer : Official... Jun 2023There is a lack of studies that systematically evaluate the clinical factors of PICC-RVT such as treatment, tumor stage, metastasis, and chemotherapy drugs in cancer... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
There is a lack of studies that systematically evaluate the clinical factors of PICC-RVT such as treatment, tumor stage, metastasis, and chemotherapy drugs in cancer patients. This study, therefore, aims to evaluate the clinical factors of catheter-related venous thrombosis in cancer patients with indwelling PICC to provide a basis for the clinical prevention and reduction of thrombosis.
METHODS
Relevant studies were retrieved from major databases (PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang Data, and China Biology Medicine disc (CMB)) and searched from their earliest available dates until July 2022. If two or more studies had the same outcome, a meta-analysis using RevMan 5.4.1 was performed. This systematic review was registered at PROSPERO (number CRD42022358426).
RESULTS
A total of 19 articles involving 19,824 patients were included for quantitative analysis. Meta-analysis of these studies indicated that a history of chemotherapy, tumor type, tumor stage, presence or absence of metastasis, and use of fluorouracil, etoposide, platinum drugs, and taxane were all risk factors for PICC catheter thrombosis in cancer patients.
CONCLUSION
In clinical PICC catheter thrombosis prevention, patients with the above characteristics should be watched more closely than other patients, as they have a higher risk for PICC catheter thrombosis. Based on the present evidence at hand, radiotherapy cannot be considered to be related to the formation of PICC-RVT in cancer patients.
Topics: Humans; Catheters; China; Databases, Factual; Etoposide; Neoplasms
PubMed: 37314592
DOI: 10.1007/s00520-023-07855-8 -
Current Medicinal Chemistry 2018Secondary metabolites from numerous plant sources have been developed as anti- cancer reagents and compounds such as resveratrol, podophyllotoxin and zerumbone are of... (Review)
Review
Secondary metabolites from numerous plant sources have been developed as anti- cancer reagents and compounds such as resveratrol, podophyllotoxin and zerumbone are of particular importance in this regard. Since their de novo chemical synthesis is both arduous and commercially expensive, there has been an impetus to develop viable, biotechnological methods of production. Accordingly, this review focuses on the recent developments in the field, highlighting the use of micropropagation, cell suspension cultures, callus cultures, hairy root cultures, recombinant microbes and genetically modified higher plants. Optimization of media and culture conditions, precursor feeding, immobilization and the use of chemical or physical elicitation in various protocols has led to an increase in resveratrol and podophyllotoxin production. Heterologous gene transformation of higher plants with stilbene synthase derived from Arachis hypogaea or Vitis vinifera lead to resveratrol production with the concomitant increase in resistance to plant pathogens. Interestingly, genetic transformation of Podophyllum hexandrum and Linum flavum with Agrobacterium rhizogenes resulted in Ri-T-DNA gene(s)-mediated enhancement of podophyllotoxin production. Zerumbone yields from tissue cultured plantlets or from suspension cultures are generally low and these methods require further optimization. In microbes lacking the native resveratrol or zerumbone biosynthesis pathway, metabolic engineering required not only the introduction of several genes of the pathway, but also precursor feeding and optimization of gene expression to increase their production. Data pertaining to safety and toxicity testing are needed prior to use of these sources of anti-cancer compounds in therapy.
Topics: Animals; Antineoplastic Agents; Bacteria; Biotechnology; Cells, Cultured; Humans; Metabolic Engineering; Plants; Podophyllotoxin; Resveratrol; Sesquiterpenes
PubMed: 28393691
DOI: 10.2174/0929867324666170404145656 -
Biotechnology Letters May 2018Endophytes are barely untapped as vital sources in the medicine. They are microorganisms which mostly exist in plants. As they are exploited, it is accepted that... (Review)
Review
Endophytes are barely untapped as vital sources in the medicine. They are microorganisms which mostly exist in plants. As they are exploited, it is accepted that endophytes can produce active metabolites that possess same function as their hosts such as taxol, podophyllotoxin, hypericin, and azadirachtin. These metabolites have been promising potential usefulness in safety and human health concerns. We are supposed to adopt measures to raise production for the low yield of metabolites. This paper summarizes the latest advances in various bioprocess optimization strategies. These techniques can overcome the limitations associated with rare pharmaceutical metabolite-producing endophytic fungi. These strategies include strain improvement, genome shuffling, medium optimization, fermentation conditions optimization, addition of specific factor, addition of solid sorbent, and co-culturing. It will enable endophytes to produce high and sustainable production of rare pharmaceutical metabolites.
Topics: Anthracenes; DNA Shuffling; Endophytes; Fermentation; Industrial Microbiology; Limonins; Metabolome; Paclitaxel; Perylene; Plants; Podophyllotoxin
PubMed: 29605937
DOI: 10.1007/s10529-018-2531-6 -
Recent Patents on Biotechnology 2017Resveratrol, taxol, podophyllotoxin, withanolides and their derivatives find applications in anti-cancer therapy. They are plant-derived compounds whose chemical... (Review)
Review
BACKGROUND
Resveratrol, taxol, podophyllotoxin, withanolides and their derivatives find applications in anti-cancer therapy. They are plant-derived compounds whose chemical structures and synthesis limit their natural availability and restrict a large-scale industrial production. Hence, their production by various biotechnological approaches may hold promise for a continuous and reliable mode of supply.
OBJECTIVE
We review process and product patents in this regard.
METHODS
Accordingly, we provide a general outline to search the freely accessible WIPO, EPO, USPTO and Cambia databases with several keywords and patent codes. We have tabulated both granted and filed patents from the said databases.
RESULTS AND CONCLUSION
We retrieved ~40 patents from these databases. Novel biotechnological processes for production of these anticancer compounds include Agrobacterium rhizogenes-mediated hairy root culture, suspension culture, cell culture with elicitors, use of recombinant microorganisms, and bioreactors among others. The results are indicative of being both database-specific as well as queryspecific. A ten-year search window yielded 33 patents. The utility of the search strategy is discussed in the light of biotechnological developments in the field. Those who examine patent literature using similar search strategies may complement their knowledge obtained from perusal of mainstream journal resources.
Topics: Humans; Neoplasms; Paclitaxel; Patents as Topic; Podophyllotoxin; Resveratrol; Stilbenes; Withanolides
PubMed: 28137207
DOI: 10.2174/1872208311666170127114804 -
Proceedings of the National Academy of... Jan 2022Deoxypodophyllotoxin contains a core of four fused rings (A to D) with three consecutive chiral centers, the last being created by the attachment of a peripheral...
Deoxypodophyllotoxin contains a core of four fused rings (A to D) with three consecutive chiral centers, the last being created by the attachment of a peripheral trimethoxyphenyl ring (E) to ring C. Previous studies have suggested that the iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase, deoxypodophyllotoxin synthase (DPS), catalyzes the oxidative coupling of ring B and ring E to form ring C and complete the tetracyclic core. Despite recent efforts to deploy DPS in the preparation of deoxypodophyllotoxin analogs, the mechanism underlying the regio- and stereoselectivity of this cyclization event has not been elucidated. Herein, we report 1) two structures of DPS in complex with 2OG and (±)-yatein, 2) in vitro analysis of enzymatic reactivity with substrate analogs, and 3) model reactions addressing DPS's catalytic mechanism. The results disfavor a prior proposal of on-pathway benzylic hydroxylation. Rather, the DPS-catalyzed cyclization likely proceeds by hydrogen atom abstraction from C7', oxidation of the benzylic radical to a carbocation, Friedel-Crafts-like ring closure, and rearomatization of ring B by C6 deprotonation. This mechanism adds to the known pathways for transformation of the carbon-centered radical in Fe/2OG enzymes and suggests what types of substrate modification are likely tolerable in DPS-catalyzed production of deoxypodophyllotoxin analogs.
Topics: Berberidaceae; Drugs, Chinese Herbal; Ligases; Oxidation-Reduction; Plant Proteins; Podophyllotoxin
PubMed: 34969844
DOI: 10.1073/pnas.2113770119