Polygodial Research Articles

Polygodial, a Sesquiterpene Dialdehyde, Activates Apoptotic Signaling in Castration-Resistant Prostate Cancer Cell Lines by Inducing Oxidative Stress.

Prostate cancer (PCa) is the second leading cause of cancer death among men in the United States. Surgery, radiation therapy, chemotherapy, and androgen deprivation therapy are currently the standard treatment options for PCa. These have poor outcomes and result in the development of castration-resistant prostate cancer (CRPC), which is the foremost underlying cause of mortality associated with PCa. Taxanes, diterpene compounds approved to treat hormonal refractory PCa, show poor outcomes in CRPC. Polygodial (PG) is a natural sesquiterpene isolated from water pepper (Persicaria hydropiper), Dorrigo pepper (Tasmannia stipitata), and mountain pepper (Tasmannia lanceolata). Previous reports show that PG has an anticancer effect. Our results show that PG robustly inhibits the cell viability, colony formation, and migration of taxane-resistant CRPC cell lines and induces cell cycle arrest at the G0 phase. A toxicity investigation shows that PG is not toxic to primary human hepatocytes, 3T3-J2 fibroblast co-cultures, and non-cancerous BPH-1 cells, implicating that PG is innocuous to healthy cells. In addition, PG induces oxidative stress and activates apoptosis in drug-resistant PCa cell lines. Our mechanistic evaluation by a proteome profiler-human apoptotic array in PC3-TXR cells shows that PG induces upregulation of cytochrome c and caspase-3 and downregulation of antiapoptotic markers. Western blot analysis reveals that PG activates apoptotic and DNA damage markers in PCa cells. Our results suggest that PG exhibits its anticancer effect by promoting reactive oxygen species generation and induction of apoptosis in CRPC cells.

Polygodial analog induces apoptosis in LNCaP prostate cancer cells

Prostate cancer (PCa) is the second leading cause of death in American men. The chemotherapeutic treatment strategies are generally not effective and can lead to side effects. Hence, there is an urgent need to identify novel chemotherapeutic agents. The aim of this study was to synthesize and evaluate the therapeutic effects of a synthetic analog of polygodial (PG), a pungent constituent abundantly present in mountain pepper, water pepper and dorrigo pepper, on LNCaP PCa cell line and its anti-cancer mechanisms in a preclinical study. We evaluated the anti-cancer potential of the PG analog namely DRP-27 using various assays such as cell viability by MTT assay, anchorage independent growth by soft agar assay, reactive oxygen species generation by 2′,7′-dichlorofluorescein probe-based fluorescence assay, and apoptosis by Annexin-V and TUNEL assays respectively. Western blot analysis was performed to identify the molecular mechanism of DRP-27-induced cell death. Our results showed that DRP-27 significantly inhibited LNCaP cell proliferation in a dose-dependent manner at 48 h treatment in vitro. In addition, DRP-27 potently inhibited anchorage-independent growth of these cells. Flow cytometry, Annexin-V and TUNEL assays confirmed that DRP-27 induces apoptosis in LNCaP cells. DRP-27 also induced the activation of intracellular reactive oxygen species. Western blot analysis revealed that DRP-27 downregulated the expression of survivin, while activating Bax and DNA damage marker pH2AX in LNCaP cells. In conclusion, our study suggests that DRP-27 might be an effective anti-cancer agent for PCa.

Abstract 4804: Polygodial: A potential sesquiterpene dialdehyde for castration-resistant prostate cancer treatment

Abstract Major cause for prostate cancer mortality is due to the development of castration-resistant prostate cancer (CRPC) which usually develops when prostate cancer patients undergo standard androgen deprivation therapy. Treatment options currently available for CRPC are not very efficient and have many side effects. Hence, there is an urgent need to identify effective treatment strategies for CRPC. Natural compounds have previously shown to be an effective alternative treatment strategy for cancer. Polygodial (PG) an active constituent of mountain pepper belonging to sesquiterpene dialdehyde family has shown to have several pharmacological benefits including anti-bacterial, anti-fungal, anti-inflammatory, and anti-cancer properties. The objective of this study is to determine the therapeutic effects of PG against CRPC in a pre-clinical study. Cell lines used in this study were androgen dependent LNCaP and CRPC C4-2, DU145, and PC-3 cells. MTT, soft agar, and wound healing assays were performed to evaluate the effects of PG respectively on cell survival, anchorage independent growth, and migration characteristics of prostate cancer cells. PC-3 cells were utilized to determine the anti-cancer mechanisms of PG. Cell viability assay results showed PG effectively inhibited cell proliferation of CRPC C4-2, DU145 and PC-3 cell lines as compared to androgen dependent LNCaP cells. PG treatment significantly reduced the colony growth of CRPC cells in soft agar plates as compared to controls which correlates with its inhibitory effect on anchorage independent growth of these cells. In addition, PG also reduced the migration potential of CRPC cells in a wound healing assay. Inhibition of anchorage independent growth and motility of PCa cells by PG suggests its tumor suppressive and anti-metastatic potential. Western blot analysis showed that PG treatment downregulated the expression of a key cell survival molecule, High mobility group box1 (HMGB1) while promoting PARP-1 cleavage in PC-3 cells. Interestingly, our results also showed that BiP/GRP78, a marker of endoplasmic reticulum (ER) stress was upregulated following PG treatment in PC-3 cells. These findings suggest that PG enforces its tumor suppressive action by inhibiting HMGB1 signaling axis with concurrent activation of ER stress pathway in CRPC cells. Taken together, our study shows that PG might be an effective chemotherapeutic natural compound especially for CRPC. Citation Format: Akshita P. Pillai, Subramanyam Dasari, Bhavani Patel, Souresh Banerjee, Alexander V. Kornienko, Gnanasekar Munirathinam. Polygodial: A potential sesquiterpene dialdehyde for castration-resistant prostate cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4804.

Polygodial: a contact active antifouling biocide

Ongoing investigation of the candidate antifouling (AF) biocide polygodial (PG) has revealed that this compound may be contact active, whereby it can confer effect while remaining bound within a stable matrix. To test this hypothesis, the AF activity of PG-laced coatings was compared to that of seawater in which PG-laced coatings had been soaked. Four coating types spanning high to low affinity for PG were examined and AF activity was assessed based on inhibition of settlement and metamorphosis of larvae of three fouling organisms: Ciona savignyi Herdman, Mytilus galloprovincialis Lamarck and Spirobranchus caraniferus Gray. Direct exposure to the coatings had a significantly greater impact on larval metamorphosis than indirect exposure to seawater in which the coatings had been soaked. In particular, metamorphosis was almost completely inhibited by high-affinity coatings containing ≥ 200 ng of PG per replicate, while corresponding soaking waters had no detectable effect. These findings support the assertion that PG is contact active.

Miogadial and miogatrial with α,β-unsaturated 1,4-dialdehyde moieties—Novel and potent TRPA1 agonists

Aims Most of the terpenoids with an α,β-unsaturated 1,4-dialdehyde moiety, which are found in plants, fungi, and insects, have a pungent taste. However, the neural receptors responsible for the pungency of these terpenoids have not been identified yet. The transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1), which are expressed in the nociceptive neurons, induce a sensation of heat on activation by some pungent ingredients in food. In this study, we selected miogadial (MD), miogatrial (MT), and polygodial (PG) from the terpenoids with an α,β-unsaturated 1,4-dialdehyde moiety and examined the effects of these 3 terpenoids on TRPA1 or TRPV1. Main methods TRPV1 and TRPA1 activity by 3 terpenoids were evaluated using Ca 2+ imaging and patch-clamp methods in mammalian cells that express TRP heterologously and mouse sensory neurons. Key findings The 3 terpenoids activated TRPA1 that was heterologously expressed in HEK293 or CHO cells. The potencies of activation by the 3 terpenoids were equal and almost 10 times stronger than that of allyl isothiocyanate (AITC), which is known as the most potent TRPA1 agonist among all natural products. Moreover, these 3 terpenoids exhibited increased intracellular Ca 2+ concentration in mouse sensory neuron cells compared to AITC. High concentrations of the 3 terpenoids also activated TRPV1 that was heterologously expressed in HEK293 cells. Significance These results indicated that MD, MT, and PG were more potent in activating TRPA1 than TRPV1, and suggested that they primarily activate TRPA1 to induce pungency.

Occurrence of polygodial in species of Polygonum genus belonging to Persicaria section

Occurrence of polygodial in species of Polygonum genus belonging to Persicaria section

Synthesis of all possible stereoisomers of polygodial

The three possible isomers of polygodial, epimers at C-9, cis and trans fused, are described. Controlled kinetic and thermodynamic epimerizations allow preparation of all stereoisomers from the same key intermediate.

Synthesis of Polygodial

Synthesis of Polygodial