Piperine: an emerging biofactor with anticancer efficacy and therapeutic potential.

Anticancer drug discovery needs serious attention to overcome the high mortality rate caused by cancer. There are still many obstacles to treating this disease, such as the high cost of chemotherapeutic drugs, the resulting side effects from the drug, and the occurrence of multidrug resistance. Herbaceous plants are a reservoir of natural compounds that can be anticancer drugs with novel mechanisms of action. Piperine, a bioactive compound derived from Piper species, is gaining attention due to its unique dual role in directly inhibiting tumor growth and enhancing the bioavailability of chemotherapeutic drugs. Unlike conventional treatments, Piperine exhibits a novel mechanism of action by modulating multiple signaling pathways, including apoptosis and autophagy, with low toxicity. Additionally, Piperine acts as a bioenhancer by improving the absorption and effectiveness of other anticancer agents, reducing the required dosage, and minimizing side effects. Therefore, this review aims to visualize a summary of Piperine sources, phytochemistry, chemical structure-anticancer activity relationship, anticancer activities of semi-synthetic derivatives, pharmacokinetic and bioavailability, in vitro and in vivo preclinical studies, mechanism of antitumor action, human clinical trials, toxicity, side effects, and safety of Piperine. References were collected from the Pubmed/MedLine database (https://pubmed.ncbi.nlm.nih.gov/) with the following keywords: "Piperine anticancer," "Piperine derivatives," "Piperine antitumor mechanism" and "Piperine pharmacokinetic and bioavailability," after filter process by inclusion and exclusion criteria, 101 were selected from 444 articles. From 2013 to 2023, there were numerous studies regarding preclinical studies of Piperine of various cell lines, including breast cancer, prostate cancer, lung cancer, melanoma, cervical cancer, gastric cancer, osteosarcoma, colon cancer, hepatocellular carcinoma, ovarian cancer, leukemia, colorectal cancer, and hypopharyngeal carcinoma. In vivo, the anticancer study has also been conducted on some animal models, such as Ehrlich carcinoma-bearing mice, Ehrlich ascites carcinoma cells-bearing Balbc mice, hepatocellular carcinoma-bearing Wistar rat, A375SM cells-bearing mice, A375P cells-bearing mice, SNU-16 cells-bearing BalbC mice, and HGC-27-bearing baby mice. Treatment with this compound leads to cell proliferation inhibition and induction of apoptosis. Piperine has been used for clinical trials of diseases, but no cancer patient report exists. Various semi-synthetic derivatives of Piperine show efficacy as an anticancer drug across multiple cell lines. Piperine shows promise for use in cancer clinical trials, either as a standalone treatment or as a bioenhancer. Its bioenhancer properties may enhance the efficacy of existing chemotherapeutic agents, providing a valuable foundation for developing new anticancer therapies.

Antioxidant, Antiinflammation, and Antifibrotic Activity of Ciplukan (Physalis angulata L). Extract.

Purpose: Physalis angulata Linn. (Ciplukan) is a plant widely used in traditional medicine in subtropical and tropical regions. Most studies focus on its antioxidant and anti-inflammatory activity. Many studies also reported its therapeutic potential for treating cancer, malaria, hepatitis, rheumatism, liver problems, and tumors, but few studies have reported its anti-fibrosis activity. Here, we aimed to investigate the potential of P. angulata as an antioxidant and anti-inflammatory that may be correlated with its anti-fibrosis action. Methods: In our study, we treated 3T3-L1 and TGF-ß-induced 3T3-L1 cells with an ethanol extract of P. angulata. We then monitored the cell's response, evaluated the antioxidant activity using an MTT assay, and observed the cells' migration using the cell scratch assay. We used RT-PCR to determine the expression of HIF-1α and IL-6 on TGF-ß-induced 3T3-L1 cells. Results: The ethanol extract of P. angulata showed antioxidant activity and promoted cell proliferation on 3T3-L1 cells. Interestingly, the extract inhibited the migration of TGF-ß-induced 3T3-L1 cells. Further analysis revealed that the extract could inhibit HIF-1α expression and suppress IL-6 expression on TGF-ß-induced 3T3-L1 cells. Conclusion: The ethanol extract of P. angulata showed antioxidant and anti-inflammation activities in 3T3-L1 cells. Both activities are associated with the antifibrotic activity of P. angulata's ethanol extract.

N-phenyl pyrazoline derivative inhibits cell aggressiveness and enhances paclitaxel sensitivity of triple negative breast cancer cells.

Protein kinase dysregulation induces cancer cell aggressiveness leading to rapid tumor progression and poor prognosis in TNBC patients. Many small-molecule kinase inhibitors have been tested in clinical trials to treat TNBC patients. In the previous study, we found that N-phenylpyrazoline small molecule acts as a protein kinase inhibitor in cervical cancer cells. However, there remains unknown about N-phenyl pyrazoline potency as a kinase inhibitor and its anti-cancer activity in TNBC cells. In this study, we investigated the activity of N-phenyl pyrazoline against TNBC cells via tyrosine kinase inhibition. Based on the MTT assay, the IC50 values for the N-phenyl pyrazoline 2, 5, A, B, C, and D against Hs578T were 12.63 µM, 3.95 µM, not available, 18.62 µM, 30.13 µM, and 26.79 µM, respectively. While only P5 exhibited the IC50 against MDA MB 231 (21.55 µM). Further, N-phenyl pyrazoline 5 treatment significantly inhibited the cell proliferation rate of Hs578T and MDA MB 231 cells. The migration assay showed that treatment with the compound N-phenyl pyrazoline 5 with 4 µM concentration significantly reduced cell migration of Hs578T cells. N-phenyl pyrazoline 5 treatment at 1 µM and 2 µM was able to reduce the tumorsphere size of Hs578t cells. A combination treatment of P5 and paclitaxel showed a synergistic effect with a combination index score > 1 in both TNBC cells. Further, the P5 predictively targeted the protein kinases that significantly correlated to breast cancer prognosis. The GSEA analysis result shows that receptor tyrosine kinase, Notch3, Notch4, and Ephrin signaling pathways were targeted by P5. The P5 treatment reduced the EGFR expression level and activation in TNBC cells.

Pyrazoline B-Paclitaxel or Doxorubicin Combination Drugs Show Synergistic Activity Against Cancer Cells: In silico Study.

Background: Multidrug resistance in various cancer types is a major obstacle in cancer treatment. The concept of a single drug molecular target often causes treatment failure due to the complexity of the cellular processes. Therefore, combination chemotherapy, in which two or more anticancer drugs are co-administered, can overcome this problem because it potentially have synergistic efficacy besides reducing resistance, and drug doses. Previously, we reported that pyrazoline B had promising anticancer activity in both in silico and in vitro studies. To increase the efficacy of this drug, co-administration with established anticancer drugs such as doxorubicin and paclitaxel is necessary. Materials and Methods: In this study, we used an in silico approach to predict the synergistic effect of pyrazoline B with paclitaxel or doxorubicin using various computational frameworks and compared the results with those of an established study on the combination of doxorubicin-cyclophosphamide and paclitaxel-ascorbic acid. Results and Discussion: Drug interaction analysis showed the combination was safe with no contraindications or side effects. Furthermore, molecular docking studies revealed that doxorubicin-pyrazoline B and doxorubicin-cyclophosphamide may synergistically inhibit cancer cell proliferation by inhibiting the binding of topoisomerase I to the DNA chain. Moreover, the combination of pyrazoline B-paclitaxel may has synergistic activity to cause apoptosis by inhibiting Bcl2 binding to the Bax fragment or inhibiting cell division by inhibiting α-ß tubulin disintegration. Paclitaxel-ascorbic acid had a synergistic effect on the inhibition of α-ß tubulin disintegration. Conclusion: The results show that this combination is promising for further in vitro and in vivo studies.

Identification of KRAS mutation and HER2 expression in Indonesian colorectal cancer population: a cross-sectional study.

In Indonesia, colorectal cancer is the third most common type. In 2008, Indonesia ranked fourth in the Association of Southeast Asian Nations (ASEAN) countries, with an incidence rate of 17.2 per 100 000 population. This figure is predicted to continue to increase from year to year. In 30% of colorectal cancer patients diagnosed after metastases, some patients will develop metastases after undergoing surgical resection of the primary tumor. The survival of metastatic colorectal cancer patients has improved significantly in the last 20 years with the introduction of target-oriented drugs, anti-epidermal growth factor receptor (EGFR), and anti-human epidermal growth factor receptor-2 (HER2). This study aims to assess the relationship between Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation and HER2 expression for targeted therapy implementation. Patients and methods: This research is a cross-sectional study. The research subjects in this study were colorectal cancer patients in the digestive surgery division. There were 58 study subjects. Examination of KRAS mutations was carried out by PCR on fresh tumor tissue obtained from surgery or colonoscopy. Meanwhile, the HER2 examination used the immunohistochemistry method of paraffin blocks for anatomical pathology examination. Results: Examination of KRAS mutations showed 28/58 (43.8%) patients with colorectal cancer, while HER2 overexpression was found in 6/58 (10.3%) patients with colorectal cancer. Univariate analysis of KRAS mutations and HER2 expression showed that four subjects with KRAS mutations had excess HER2 expression (P=0.341). Conclusion: There is no association between KRAS mutations and HER2 overexpression in colorectal cancer patients.

Breynia cernua: Chemical Profiling of Volatile Compounds in the Stem Extract and Its Antioxidant, Antibacterial, Antiplasmodial and Anticancer Activity In Vitro and In Silico.

Breynia cernua has been used as an alternative medicine for wounds, smallpox, cervical cancer, and breast cancer. This plant is a potential source of new plant-derived drugs to cure numerous diseases for its multiple therapeutic functions. An in vitro study revealed that the methanol extract of B. cernua (stem) exhibits antioxidant activity according to DPPH and SOD methods, with IC50 values of 33 and 8.13 ppm, respectively. The extract also exerts antibacterial activity against Staphylococcus aureus with minimum bactericidal concentration of 1875 ppm. Further analysis revealed that the extract with a concentration of 1-2 ppm protects erythrocytes from the ring formation stage of Plasmodium falciparum, while the extract with a concentration of 1600 ppm induced apoptosis in the MCF-7 breast cancer cell line. GC-MS analysis showed 45 bioactive compounds consisting of cyclic, alkyl halide, organosulfur, and organoarsenic compounds. Virtual screening via a blind docking approach was conducted to analyze the binding affinity of each metabolite against various target proteins. The results unveiled that two compounds, namely, N-[ß-hydroxy-ß-[4-[1-adamantyl-6,8-dichloro]quinolyl]ethyl]piperidine and 1,3-phenylene, bis(3-phenylpropenoate), demonstrated the best binding score toward four tested proteins with a binding affinity varying from -8.3 to -10.8 kcal/mol. Site-specific docking analysis showed that the two compounds showed similar binding energy with native ligands. This finding indicated that the two phenolic compounds could be novel antioxidant, antibacterial, antiplasmodial, and anticancer drugs. A thorough analysis by monitoring drug likeness and pharmacokinetics revealed that almost all the identified compounds can be considered as drugs, and they have good solubility, oral bioavailability, and synthetic accessibility. Altogether, the in vitro and in silico analysis suggested that the extract of B. cernua (stem) contains various compounds that might be correlated with its bioactivities.

The Use of Biomaterials in Three-Dimensional Culturing of Cancer Cells.

Cell culture is an important tool in biological research. Most studies use 2D cell culture, but cells grown in 2D cell culture have drawbacks, including limited cell and cell-extracellular matrix interactions, which make it inaccurate to model conditions in vivo. Anticancer drug screening is an important research and development process for developing new drugs. As an experiment to mimic the cancer environment in vivo, several studies have been carried out on 3-dimensional (3D) cell cultures with added biomaterials. The use of hydrogel in 3D culture cells is currently developing. The type of hydrogel used might influence cell morphology, viability, and drug screening outcome. Therefore, this review discusses 3D cell culture research regarding the addition of biomaterials.

Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione.

Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion.