LONG PEPPER

Long pepper is the common pepper with roots in ayurveda, used widely to enhance absorption of many natural compounds, most famously curcumin derived from tumeric root. Evidence from clinical trials is mainly its anti-inflammatory, immune system health improvements. Mostly long pepper is useful together with other natural compounds, especially curcumin

Its active ingredients include piperlongumine and piperine. There is a large weight of pre-clinical laboratory results showing direct actions against many cancers, but its own absorption and reach limits the evidence in full clinical trials, so far. More advanced supplement formulas can help absorption.

EXAMPLES OF IMPROVED OUTCOMES

PRE-DIAGNOSIS OR PREVENTION

Highlighted Studies

We demonstrate that piperlongumine inhibits cell proliferation, regulates the cell cycle, and induces cellular apoptosis in various types of human thyroid cancer cells. The antihuman thyroid cancer activity of piperlongumine was through ROS induction, and it further suppressed the downstream Akt signaling pathway to elevate mitochondria-dependent apoptosis. A mouse xenograft study demonstrated that piperlongumine was safe and could inhibit tumorigenesis in vivo. The present study provides str...

PL inhibited the activation and proliferation of primary human T cells after costimulation through CD3 and CD28. In particular, the development of proinflammatory T_H17 cells was significantly diminished, while anti-inflammatory T_reg cells were upregulated…our data demonstrate that PL acts as an immunomodulating agent for primary human T cells. By altering the redox balance toward a prooxidative milieu PL shifts T cell immunity toward an immunosuppressive phenotype....

To improve the anti-tumor of sorafenib [oncology drug], we demonstrate that piperlongumine (PL), an alkaloid isolated from the fruits and roots of Piper-longum L., enhances the cytotoxicity of sorafenib….our data indicate that PL displays potential synergistic anti-tumor in combination with sorafenib in liver cancer.

The anti-cancer property of PL against different types of cancers has been studied in detail in in vitro and in vivo settings. The ability of PL to modulate the important cell signaling pathways such as PI3K/Akt/ mTOR, NF-κB, JAK/ STAT3, and ERK suggests that this compound is effective in modulating the important hallmarks of cancer, including cell survival, proliferation, invasion, migration, EMT, metastases, and angiogenesis.

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TABLE OF REFERENCES

URL	Pepper type	Category	Highlight	Highlight 2	Dose mg/kg
https://www.frontiersin.org/articles/10.3389/fonc.2019.01345/full	Piperlongumine	Lab study	Here, we demonstrate that PL induces the rapid depletion of survivin protein levels via reactive oxygen species (ROS)-mediated proteasome-dependent pathway in vitro, while exerting a remarkable inhibitory influence on the proliferation of ovarian cancer cells. Overexpression of survivin raises the survival rate of ovarian cancer cells to Piperlongumine. Moreover, PL inhibits ovarian cancer cells xenograft tumor growth and downregulates survivin in vivo	Our findings reveal a previously unrecognized mechanism of PL in suppressing survivin expression as well as survivin promotes piperlongumine resistance in ovarian cancer and suggest that ROS-mediated proteasome-dependent pathway can be exploited to overcome apoptosis resistance triggered by aberrant expression of survivin.	60mg/kg
https://www.nature.com/articles/srep26357/figures/7	Piperlongumine	Lab study	Piperlongumine showed the most significant cell growth inhibitory effect and the best NF-κB binding affinity. In conclusion, PL could inhibit lung tumor growth via activation of Fas and DR4, and inhibition of NF-κB signaling pathway in vivo and in vitro. Because PL is selectively toxic to cancer cells with high drug-likeness and permeability, it may be a promising anti-cancer agent with little side effect for treatment of lung cancer.	We performed animal experiments with xenograft nude mice model. The present data showed that PL suppressed lung tumor growth, tumor volume and tumor weight in a dose dependent manner (2.5–5 mg/kg). Besides, Western blotting data showed that the expression of apoptotic proteins such as Bax, cleaved caspase-3, cleaved caspase-8, Fas and DR4 was increased while the expression of anti-apoptotic protein Bcl-2 was decreased in a dose dependent manner (2.5–5 mg/kg)
https://www.sciencedirect.com/science/article/pii/S0006291X13009868#s0010	Piperlongumine	Lab study	Considering the central role of the LMP1–NF-κB–Myc axis in B-lineage neoplasia, these findings further our understanding of the mechanisms by which PL inhibits B-lymphoma and provide a preclinical rationale for the inclusion of PL in new interventions in blood cancers	Given that two hallmarks of cancer are sustained proliferation and evasion of apoptosis [36], our data suggest that LMP1–NF-κB–Myc-driven expression of Aurka, Bub1b and Ccnb1 is important for maintaining the former, whereas expression of Cdkn1a, Fancd2, Xrcc6 and perhaps Chek1 enables the latter in BL-like tumors.....PL appears to target both hallmarks of cancer, lending credence to the proposition that the compound may afford new approaches to the chemoprevention and treatment of blood cancers.
https://www.sciencedirect.com/science/article/abs/pii/S1043661822000858	Piperlongumine	Lab study- adjunct	Piperlongumine synergistically enhances the anticancer effects of sorafenib, highlighting a novel therapeutic avenue in liver cancer. We found that PL enhances the anticancer activity of sorafenib in liver cancer cells primarily through ROS-dependent mitochondrial dysfunction and apoptosis as well as cell cycle arrest.	Sorafenib has been demonstrated to exert antitumour activity by inhibiting cell proliferation and tumour angiogenesis as well as inducing apoptosis in liver cancer. However, liver cancer cells display remarkable adaptability to sorafenib via various innate or acquired mechanisms [6]. The capability of dismantling excess ROS is one mechanism by which liver cancer cells develop resistance to sorafenib therapy under conditions of oxidative stress
https://aacrjournals.org/mct/article/13/10/2422/128915/Piperlongumine-Chemosensitizes-Tumor-Cells-through	Piperlongumine	Lab study- adjunct , Lab study	Many cancer therapies indirectly activate apoptosis by chemically or physically damaging DNA. This damage may have the unintended effect of generating a pool of heavily mutated cancer cells and increasing the chances of their developing resistance. We showed that piperlongumine potentiated cell death induced by TNFα or the chemotherapeutic agents 5-FU and bortezomib in KBM-5 cells. Our results suggest that chemotherapy or radiotherapy followed by treatment with piperlongumine could reduce the tumor burden	Inhibition in NF-κB activity downregulated the expression of proteins involved in cell survival (Bcl-2, Bcl-xL, c-IAP-1, c-IAP-2, survivin), proliferation (c-Myc, cyclin D1), inflammation (COX-2, IL6), and invasion (ICAM-1, -9, CXCR-4, VEGF). Overall, our results reveal a novel mechanism by which piperlongumine can exhibit antitumor activity through downmodulation of proinflammatory pathway
https://www.mdpi.com/2072-6694/13/17/4266	Piperlongumine	Lab study	An intrinsic caspase-dependent apoptosis pathway was observed in the Thyroid cancer cells under Piperlongumine treatment. The activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL. PL-mediated apoptosis in TC cells was through the ROS-Akt pathway. Finally, the anticancer effect and safety of PL were also demonstrated in vivo. Our findings indicate that PL exhibits antitumor activity and has the potential for use as a chemotherapeutic agent against TC	Previous research has indicated that PL is highly selective in targeting cancer cells, but not healthy cells [7]. Furthermore, a good safety profile has been observed in previous in vivo toxicological testing, showing high absorption through the gastrointestinal tract and >50% of bioavailability after oral administration of PL in mice [32]. The effects of PL on various molecular targets involved in cancer development and progression have been reported, focusing on its low toxicity and advanced pharmacokinetic features	5 and 10mg/ kg
https://www.explorationpub.com/Journals/etat/Article/100249	Piperlongumine	Meta-analysis	Recently, the focus was driven towards developing [Piperlongumine] as a chemosensitizer and radiosensitizer which sensitized the cancer cells towards the commercially available chemotherapeutics including cisplatin, doxorubicin, 5-FU, gemcitabine, oxaliplatin, and PTX, and ionization/X-ray radiation. PL was found to sensitize the cancer cells to chemotherapeutics and radiation by acting on the cell signaling pathways and genes associated with chemo and radioresistance, inhibiting the biotransformation of the drugs into less active metabolites, and suppressing the properties of cancer stem cells	The anti-cancer property of PL against different types of cancers has been studied in detail in in vitro and in vivo settings. The ability of PL to modulate the important cell signaling pathways such as PI3K/Akt/ mTOR, NF-κB, JAK/ STAT3, and ERK suggests that this compound is effective in modulating the important hallmarks of cancer, including cell survival, proliferation, invasion, migration, EMT, metastases, and angiogenesis. The multi-targeted and pleiotropic nature of PL suggested that it might also be able to regulate complex phenomena such as chemoresistance and radioresistance
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087272/	Piperlongumine	Lab study	In conclusion, PL and VC [ intravenous vitamin c] showed antiproliferative properties against GC cells and this effect was significantly enhanced when the two agents were combined. PL promoted ROS as well as reversing the abnormal activation of STAT3 caused by VC, which could be the key mechanism of action of this combination. This would be expected to overcome chemotherapy resistance. Therefore, the combination of PL and VC as an adjuvant provides a new strategy in future GC chemotherapy.	Among the many small molecules that can inhibit the activation of STAT3, PL has attracted the attention of researchers due to its good effectiveness and safety. 16 PL has broad-spectrum anticancer activity while showing less toxicity to normal cells. 35 In addition, the effective inhibition of STAT3 activation by PL suggests that it has the potential to improve chemotherapy resistance. 36 In the present study, PL and VC showed opposite regulatory effects on p-STAT3. PL effectively inhibited the activation of STAT3 in both GC cells, which was consistent with previous studies
https://www.oncotarget.com/article/2402/text/	Piperlongumine	Lab study	In conclusion, our data suggest that PL induces ROS accumulation and cell death selectively in HNC cells by targeting critical regulators of ROS homeostasis. The study also revealed that PL can trigger HNC cell death via JNK and PARP activation, which is a novel mechanism. Further, PL can enhance the cytotoxicity of cisplatin in both p53-wild-type and p53-mutant HNC cells. This study supports the need for further investigation of PL as a potential cancer therapy, particularly for HNC with aggressive phenotypes.	PL induces cell cycle arrest and inhibits angiogenesis and metastasis in cancer cells regardless of p53 status [14, 35]. PL sensitizes p53-mutant HNC cells to cisplatin, leading to increased cytotoxicity and more effective therapy for aggressive HNC. In addition, our data showed that PL did not have any apparent adverse effects in vivo. Taken together, these findings may be of paramount clinical significance: by inducing the death of cells with ROS accumulation, PL could reduce the dose of cisplatin required in the clinical setting and thereby minimize the potential adverse effects of cisplatin chemotherapy.
https://go.gale.com/ps/i.do?p=AONE&u=googlescholar&id=GALE\|A526870634&v=2.1&it=r&sid=googleScholar&asid=8a9772ff		Lab study
https://jeccr.biomedcentral.com/articles/10.1186/s13046-023-02686-1#	Piperlongumine	Lab study- adjunct	RT/TMZ/PL [piperlongumine adjuvant to oncology] combinations resumed ROS level by resetting ROSgen/ROSsca, exacerbated oxidative stress-induced cell death, enhanced inflammatory and immune responses (including IFN TAMs, CD8+ T cells), thus converted “cold” tumor microenvironment to “hot” and produced curable efficacy (Fig. 8). αPD-1 blocked RT/TMZ/PL-induced PD-1/PD-L1 inhibitory function, thus RT/TMZ/PL/αPD1 achieved 50% of cure or 25% of immune cure in G422TN-mice. These results verified the refractoriness of GBM and strongly suggest clinical trials of RT/TMZ/PL/αPD1 regimen in GBM patients.
https://www.tandfonline.com/doi/full/10.1080/01635581.2020.1825755	Piperlongumine	Lab study	Piperlongumine also inhibited transforming growth factor β-induced ZEB1 and Slug expression. ROS accumulated in piperlongumine-treated cells, while changes in metastasis-associated gene expression were ablated by exogenous glutathione. Metastasis of 4T1 cells to the lungs of BALB/c mice was dramatically reduced in piperlongumine-treated animals. These findings reveal a previously unknown capacity of low dose piperlongumine to interfere with TNBC metastasis via an oxidative stress-dependent mechanism	In this study, we determined the effect of low dose piperlongumine on the motility/invasive capacity and epithelial-to-mesenchymal transition (EMT) of MDA-MB-231 triple-negative breast cancer (TNBC) cells and the metastasis of 4T1 mouse mammary carcinoma cells. MTT assays measured the effect of piperlongumine on TNBC cell growth. Motility/invasiveness were determined by gap closure/transwell assays. Western blotting assessed ZEB1, Slug, and matrix metalloproteinase (MMP) 9 expression.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428232/	Piperlongumine	Lab study	Our findings demonstrate that PL exhibits antitumor activity against TC [thyroid cancer] cell lines, including ATC and multiple drug-resistant PTC and FTC cells, by inhibiting cell proliferation, enhancing G2/M phase arrest, and promoting apoptosis. In addition, PL can trigger TC cell death through intrinsic cellular apoptosis by ROS induction and inhibition of downstream Akt signaling. This is the first study to report that TC cell lines are sensitive to PL. The study also investigated the anti-TC mechanisms of PL in detail, which suggested that it is a potential chemotherapeutic agent for TC treatment.	We demonstrate that piperlongumine inhibits cell proliferation, regulates the cell cycle, and induces cellular apoptosis in various types of human thyroid cancer cells. The antihuman thyroid cancer activity of piperlongumine was through ROS induction, and it further suppressed the downstream Akt signaling pathway to elevate mitochondria-dependent apoptosis. A mouse xenograft study demonstrated that piperlongumine was safe and could inhibit tumorigenesis in vivo. The present study provides strong evidence that piperlongumine can be used as a therapeutic candidate for human thyroid cancers.