Draft:Picropodophyllin (PPP)
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| IUPAC name
(5R,5aR,8aS,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
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| Properties | |
| C22H22O8 | |
| Molar mass | 414.410 g·mol−1 |
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| GHS labelling:[1] | |
 
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| H301, H312, H315, H319, H335 | |
| P261, P264, P264+P265, P270, P271, P280, P301+P316, P302+P352, P304+P340, P305+P351+P338, P317, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, P501 | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Picropodophyllin is a non-toxic small molecule inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF1R). It is a stereoisomer of the molecule podophyllotoxin (PPT) which also acts as an inhibitor of the IGF1R. Both stereoisomers are classified as cyclolignans, with PPT being the trans conformation and picropodophyllin being the cis conformation (Girnita et al.).
Picropodophyllin is currently being applied in clinical research investigating its viability as an anti-cancer treatment. It is often administered orally in patients with solid tumours. It has shown effectiveness in reducing tumour volume in Glioblastoma, Rhabdomyosarcoma, and other cancers through the targeting of IGF1R (Tarnowski et al.).
Synthesis[edit]
Picropodophyllin is a lignan extract from podophyllum resin which is sourced from the roots of podophyllum plants (Picropodophyllin | Ligand Page | IUPHAR/BPS Guide to PHARMACOLOGY).
Clinical Applications[edit]
Picropodophyllin has been used in multiple in-vitro and in-vivo trials investigating its ability to reduce solid tumour volume. Its current primary use is in clinical trials.
Administration[edit]
Picropodophyllin is a relatively non-polar compound, and therefore is administered clinically dissolved in solution or in drug form. In-vitro trials used saline, DMSO, or ethanol to dissolve the picropodophyllin before administering to cell cultures. In-vivo experiments used saline. Clinical trials have also used AXL1717, which is a drug containing picropodophyllin (Girnita et al.).
Glioblastoma[edit]
Picropodophyllin has been used in in-vitro and in-vivo testing on glioblastoma (GB) cells. In GB cell lines that were cultured and treated with Picropodophyllin, it was demonstrated that picropodophyllin prevents GB cell growth and induces apoptosis (Yin et al.). One in-vitro assay demonstrated that out of 12 GB cell lines, all but one had their growth inhibited by the administration of picropodophyllin (Yin et al.). Furthermore, an in-vivo assay was conducted which determined that in mice which had xenografted GB tumour cells, picropodophyllin induced strong regression of the xenograft tumours (Yin et al.).
Astrocytoma[edit]
A phase 1 clinical trial was conducted on patients suffering from recurrent or progressive malignant astrocytomas. AXL1717, a drug whose main active compound is picropodophyllin, was administered orally at a dosage of 215-400mg on a 35 day cycle (28 days administered and 7 days off).
9 patients received treatment, with 4 of them showing tumour responses to the Picropodophyllin. The trail also found that the adverse reaction to picropodophyllin, which was neutropenia, was easily detected and reversed in all but one patient (Aiken et al.).
Rhabdomyosarcoma[edit]
Rhabdomyosarcoma is a cancer that highly expresses IGF1R receptors. In-vitro studies have been conducted to investigate the viability of picropodophyllin as a treatment. In in-vitro cell cultures, certain lines of rhabdomyosarcoma such as RH30 showed 90% of cells had expression of IGF1R (Tarnowski et al.).
When treating cell cultures of RH30 and RD with picropodophyllin, researchers found that 24 hour exposure caused a dose dependent decrease in viable cancer cells. Doses above 2μM caused massive apoptosis and cell death (Tarnowski et al.).
Mechanism of Action[edit]
Currently, the specific molecular mechanisms by which picropodophyllin is able to cause apoptosis in cancer cells is unknown. Picropodophyllin suppresses signalling in the IGF1R pathway, which can be observed clinically through a reduction of phosphorylated IGF1R proteins, as well as a reduction of phosphorylated down-stream signalling proteins (Waraky et al.).
It has also been demonstrated that picropodophyllin interacts with the PI3K/Akt pathway (Dong et al.), which mediates neoplastic transformation, apoptosis, and cell cycle progression (Chang et al.). Specifically, picropodophyllin induces apoptosis and cell cycle arrest using ROS (reactive oxygen species) generation and inhibition of the PI3K/Akt pathway (Zhu et al.).
In-vitro investigations show that administration of picropodophyllin significantly increases the expression levels of ROS generating enzymes, including nicotinamide adenine dinucleotide phosphate (NADPH), oxidases (NOX1 and NPX3) and the cytochrome b-245 beta chain (CYBB). The expression of ROS scavenging enzymes remained constant post treatment, resulting in the accumulation of ROS (Zhu et al.). ROS accumulation has also been demonstrated to inactivate the PI3K/Akt pathway (Chang et al.).
Picropodophyllin’s ability to cause mitotic arrest in cancer cells is a result of inhibition of microtubule formation (Sun et al.). Researchers found that in cells which had been arrested in metaphase, the impact of picropodophyllin administration was like that of Nocodazole, a microtubule destabiliser (Waraky et al.). Picropodophyllin does not directly bind b-tubulin in microtubules, instead mediating mitotic arrest by interfering with microtubule dynamics.
Side Effects[edit]
Picropodophyllin can cause adverse effects, primarily being febrile neutropenia (NCATS Inxight Drugs — PICROPODOPHYLLIN). However, these adverse effects have been reversed in trials.
What makes picropodophyllin a compelling compound for investigation in cancer treatment is its clinical activity accompanied by a lack of metabolic toxicity (Wu et al.).
References[edit]
Aiken, Robert, et al. ‘Phase I Clinical Trial of AXL1717 for Treatment of Relapsed Malignant Astrocytomas: Analysis of Dose and Response’. Oncotarget, vol. 8, no. 46, Sept. 2017, pp. 81501–10. PubMed Central, https://doi.org/10.18632/oncotarget.20662.
Chang, F., et al. ‘Involvement of PI3K/Akt Pathway in Cell Cycle Progression, Apoptosis, and Neoplastic Transformation: A Target for Cancer Chemotherapy’. Leukemia, vol. 17, no. 3, 3, Mar. 2003, pp. 590–603. www.nature.com, https://doi.org/10.1038/sj.leu.2402824.
Dong, Lin, et al. ‘Picropodophyllin Inhibits Type I Endometrial Cancer Cell Proliferation via Disruption of the PI3K/Akt Pathway’. Acta Biochimica et Biophysica Sinica, vol. 51, no. 7, July 2019, pp. 753–60. Silverchair, https://doi.org/10.1093/abbs/gmz055.
Girnita, Ada, et al. ‘Cyclolignans as Inhibitors of the Insulin-Like Growth Factor-1 Receptor and Malignant Cell Growth’. Cancer Research, vol. 64, no. 1, Jan. 2004, pp. 236–42. Silverchair, https://doi.org/10.1158/0008-5472.CAN-03-2522.
NCATS Inxight Drugs — PICROPODOPHYLLIN. https://drugs.ncats.io/drug/0F35AOI227. Accessed 10 Dec. 2023.
Picropodophyllin | Ligand Page | IUPHAR/BPS Guide to PHARMACOLOGY. https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=7873. Accessed 10 Dec. 2023.
Sun, Rong, et al. ‘Picropodophyllin Inhibits the Growth of Pemetrexed-Resistant Malignant Pleural Mesothelioma via Microtubule Inhibition and IGF-1R-, Caspase-Independent Pathways’. Translational Lung Cancer Research, vol. 11, no. 4, Apr. 2022. tlcr.amegroups.org, https://doi.org/10.21037/tlcr-21-765.
Tarnowski, Maciej, et al. ‘Picropodophyllin (PPP) Is a Potent Rhabdomyosarcoma Growth Inhibitor Both in Vitro and in Vivo’. BMC Cancer, vol. 17, Aug. 2017, p. 532. PubMed Central, https://doi.org/10.1186/s12885-017-3495-y.
Waraky, Ahmed, et al. ‘Picropodophyllin Causes Mitotic Arrest and Catastrophe by Depolymerizing Microtubules via Insulin-like Growth Factor-1 Receptor-Independent Mechanism’. Oncotarget, vol. 5, no. 18, July 2014, pp. 8379–92.
Wu, Xuping, et al. ‘Alternative Cytotoxic Effects of the Postulated IGF-IR Inhibitor Picropodophyllin In Vitro’. Molecular Cancer Therapeutics, vol. 12, no. 8, Aug. 2013, pp. 1526–36. Silverchair, https://doi.org/10.1158/1535-7163.MCT-13-0091.
Yin, Shucheng, et al. ‘Targeting the Insulin-like Growth Factor-1 Receptor by Picropodophyllin as a Treatment Option for Glioblastoma’. Neuro-Oncology, vol. 12, no. 1, Jan. 2010, pp. 19–27. Silverchair, https://doi.org/10.1093/neuonc/nop008. Zhu, Xuejie, et al. ‘Picropodophyllin Inhibits the Proliferation of Human Prostate Cancer DU145 and LNCaP Cells via ROS Production and PI3K/AKT Pathway Inhibition’. Biological and Pharmaceutical Bulletin, vol. 45, no. 8, Aug. 2022, pp. 1027–35. DOI.org (Crossref), https://doi.org/10.1248/bpb.b21-01006.
- ^ "Picropodophyllin". pubchem.ncbi.nlm.nih.gov.