Podophyllotoxin: History, Recent Advances and Future Prospects

Shah, Zinnia; Gohar, Umar Farooq; Jamshed, Iffat; Mushtaq, Aamir; Mukhtar, Hamid; Zia-Ui-Haq, Muhammad; Toma, Sebastian; Manea, Rosana; Moga, Marius; Popovici, Bianca

doi:10.3390/biom11040603

Cited by 92 publications

(58 citation statements)

References 120 publications

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“…Ketotifen is a histamine H1 receptor antagonist and used as an anti-allergic compound but not suitable for oral administration due to its acute toxicity 18 . Podophyllotoxin is used for many years for topical treatment of warts and for cancer recently due to its activity in inducing cell cycle arrest 19 , 20 . Some drugs, such as streptomycin and methyldopate, are clinically applicable but have frequent or severe side effects after long-term application 21 , 22 .…”

Section: Resultsmentioning

confidence: 99%

Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm

et al. 2022

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Abdominal aortic aneurysm (AAA) is a lethal cardiovascular disease, and there is no proven drug treatment for this condition. In this study, by using the Connectivity Map (CMap) approach, we explored naringenin, a naturally occurring citrus flavonoid, as a putative agent for inhibiting AAA. We then validated the prediction with two independent mouse models of AAA, calcium phosphate (CaPO4)-induced C57BL/6J mice and angiotensin II-infused ApoE−/− mice. Naringenin effectively blocked the formation of AAAs and the progression of established AAAs. Transcription factor EB (TFEB) is the master regulator of lysosome biogenesis. Intriguingly, the protective role of naringenin on AAA was abolished by macrophage-specific TFEB depletion in mice. Unbiased interactomics, combined with isothermal titration calorimetry (ITC) and cellular thermal shift assays (CETSAs), further revealed that naringenin is directly bound to 14-3-3 epsilon blocked the TFEB-14-3-3 epsilon interaction, and therefore promoted TFEB nuclear translocation and activation. On one hand, naringenin activated lysosome-dependent inhibition of the NLRP3 inflammasome and repressed aneurysmal inflammation. On the other hand, naringenin induced TFEB-dependent transcriptional activation of GATA3, IRF4, and STAT6 and therefore promoted reparative M2 macrophage polarization. In summary, naturally derived naringenin or macrophage TFEB activation shows promising efficacy for the treatment of AAA.

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Section: Resultsmentioning

confidence: 99%

Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm

et al. 2022

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“…Natural products possess abundant resources for new anti-cancer drug development due to their diverse chemical structures and potent biological activities 14 - 16 . Podophyllotoxin (PPT) is a natural aryl tetrahydrolignin isolated from the plant Podophyllum 17 . Recent studies have shown that PPT has potent anti-tumor activities and a broader anti-tumor spectrum 18 .…”

Section: Introductionmentioning

confidence: 99%

TME-targeting theranostic agent uses NIR tracking for tumor diagnosis and surgical resection and acts as chemotherapeutic showing enhanced efficiency and minimal toxicity

Xu¹,

Qian²,

Meng³

et al. 2022

Theranostics

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Rationale: Precise diagnosis and effective therapy of the tumor microenvironment (TME) remains a challenge. Fluorescence tracers for monitoring primary tumors are currently reported; however, they face challenges in accurately delineating tumors in real-time during surgery, including interference from the background and insufficient accumulation of imaging reagents at tumor sites. Additionally, although the natural product podophyllotoxin (PPT) had potent and broad anti-tumor activity, the poor tumor target specificity and high toxicity of PPT extremely limited its clinical application. Methods: In the current study, a novel theranostic agent PBB was designed and synthesized by coupling the natural chemotherapeutic drug PPT with a near-infrared (NIR) fluorescence probe hemicyanine (CyOH) via redox-responsive thiolactate linker and introducing biotin to CyOH to enhance the active target ability. The activation mechanism of PBB was characterized by absorption spectra, fluorescence spectra, and HPLC. Subsequently, we investigated its imaging action, anti-tumor activity, and toxicity in vitro and in vivo . Results: In vitro experiments, PBB was verified to possess a ROS/GSH-responsive molecular switch, impelling PBB to release a fluorescent fragment and active drug PPT and selectively lighting up tumor cells but not the normal cells. As such, PBB was demonstrated to selectively inhibit the growth of tumor cells by inducing intracellular accumulation of ROS and MMP depolarization. More importantly, PBB significantly suppressed hepatic tumor growth and minimized the adverse effects caused by PPT, including acute toxicity and impaired liver function. Finally, the NIR fluorescence accumulated in the tumor tissue and stayed continuous for over 24h, and PBB provided precise visualization and highly selective fluorescence diagnosis to guide tumor resection. Conclusions: Therefore, the multilevel targeting theranostic agent provided a novel tool for precise diagnosis, real-time monitoring, and efficient tumor chemotherapy with high safety.

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“…Today, these drugs belong to the golden standards in the therapy of lung, breast, ovarian, testicular, stomach, bladder, pancreatic, brain, blood cancers [ 16 , 17 , 18 ] etc. The combination of PPT with cisplatin has been useful in the treatment of neuroblastoma and the combination of PPT derivatives with interferon has shown efficacy against genital infections [ 19 ]. PPT analogs have been applied to treat other infections, such as malaria, psoriasis, etc.…”

Section: Introductionmentioning

confidence: 99%

Junipers of Various Origins as Potential Sources of the Anticancer Drug Precursor Podophyllotoxin

et al. 2021

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Juniper representatives are natural sources of plenty of bioactive metabolites and have been used since ancient times as folk remedies against tapeworms, warts, cancer, etc. The antiproliferative activities of junipers are attributed to podophyllotoxin (PPT), which is a precursor for the synthesis of efficient anticancer drugs. However, the natural sources of PPT, Sinopodophyllum hexandrum (Royle) T. S. Ying and Podophyllum peltatum L., are already endangered species because of their intensive industrial exploitation. Therefore, identification of other sources of PPT is necessary. This study is a broad comparative investigation of junipers, for which original sources have been accessed from different continents of the world. The present research is aimed at the identification of species, producing PPT and other lignans at concentrations that are sufficient for the high antiproliferative activity of the corresponding extracts. Cytotoxic juniper leaf extracts demonstrated a broad spectrum of activity on a panel of cancer cell lines. The antiproliferative properties of junipers were attributed to the combined activity of great diversity of lignans (podophyllotoxin, deoxypodophyllotoxin, β-peltatin, yatein, matairesinol, anhydropodorhizol, etc.), detected by UHPLC-HRMS and LC-ESI-MS/MS in the corresponding extracts. Several species of the genus Juniperus L. were outlined as perspective sources of drug precursors with potential pharmaceutical applications.

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Podophyllotoxin: History, Recent Advances and Future Prospects

Cited by 92 publications

References 120 publications

Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm

Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm

TME-targeting theranostic agent uses NIR tracking for tumor diagnosis and surgical resection and acts as chemotherapeutic showing enhanced efficiency and minimal toxicity

Junipers of Various Origins as Potential Sources of the Anticancer Drug Precursor Podophyllotoxin

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