Scientific Studies has printed a examine that used a computational strategy to establish natural senotherapeutics that have a similar impact on gene expression as a known senotherapeutic drug, dasatinib [1].
Drug mixtures for higher therapies
Cellular senescence, a state through which cells can’t divide anymore however are nonetheless metabolically lively and sometimes show senescence-associated secretory phenotype (SASP), is likely one of the Hallmarks of Aging.
Senotherapeutics are medication that purpose to deal with the issue of mobile senescence. These medication would possibly goal completely different mobile processes or proteins by immediately slowing the senescent course of, killing senescent cells, or modifying the SASP.
Since every senotherapeutic might need a special mechanism of motion, it’s cheap to imagine that combining two or extra results in higher therapeutic outcomes, as each addresses the issue of senescence from completely different views.
Up to now, probably the most generally examined senolytic mixture is the antitumor drug and tyrosine-kinase inhibitor dasatinib together with the polyphenol quercetin, which is usually present in edible vegetation [2]. Sadly, dasatinib exercise regularly results in hostile uncomfortable side effects, comparable to pores and skin irritation, fluid retention, discount in blood cell manufacturing, and diarrhea [3]. Thus, researchers have sought a substitute with related properties however minimal uncomfortable side effects.
Looking for gene expression similarities
On this paper, the authors used computational approaches to establish pure senotherapeutic candidates which have related properties to dasatinib. They adopted a computational strategy as they consider that conventional drug discovery strategies are “time-consuming, expensive, and labor-intense course of with excessive failure charges” [4].
One such computational strategy, drug repurposing, can use details about current medication to seek out new purposes for them [5]. On this case, the authors aimed to establish a drug that induces a gene expression profile much like dasatinib. They hypothesized that if medication induce related gene expression profiles, they most certainly act in an analogous technique to deal with a given situation.
The authors recognized dasatinib research that analyzed and publicly shared gene expression knowledge following the dasatinib therapy. These included research of leukemia, prostate, and breast most cancers cell strains. Based mostly on this knowledge, they recognized differentially expressed genes impacted by desatinib therapy. They centered particularly on the senescence- and aging-associated genes.
Following this, the authors computationally searched by databases containing over one million gene expression profiles exhibiting responses of human cell strains to therapies with completely different chemical brokers [6]. Their purpose was to seek out dasatinib analogs and, primarily based on gene expression similarities, hypothesize concerning the potential mechanisms of motion that dasatinib and newly discovered medication share.
Utilizing the three completely different datasets, they recognized a number of candidates and manually curated the listing to decide on the pure compounds. These included piperlongumine, parthenolide, curcumin, and phloretin, with piperlongumine being probably the most promising candidate. These compounds are all present in widespread meals.
Killing by apoptosis
The authors’ evaluation instructed that “mechanisms of piperlongumine are associated to senescence and apoptosis,” a means of programmed cell dying. The authors acknowledge that they used most cancers cell line datasets for the evaluation. Nevertheless, in addition they level out that most cancers and senescent cells share some pro-survival pathways. Since quite a few research have investigated the mechanism of apoptosis induction by piperlongumine in most cancers cells [7, 8], these research and their knowledge collectively make a stronger case to recommend that piperlongumine works by inducing apoptosis in senescent cells [9].
The authors additionally convey up some further advantages of piperlongumine. The protection and efficacy of this pure compound have been beforehand examined with promising outcomes [7]. Different research have discovered that it’s poisonous to most cancers cells and senescent cells with non-significant toxicity in direction of completely different cells [9].
Concerning the remaining three compounds the authors recognized, phloretin, parthenolide, and curcumin, they didn’t completely examine the printed literature to know their mechanism of motion, however their outcomes once more instructed associations with apoptosis, particularly within the case of curcumin.
The necessity for in vivo validation
The researchers acknowledge that this examine has its limitations, the principle one being it’s a computational examine, and additional validation of their leads to preclinical and medical trials is crucial to determine the therapeutic potential of recognized compounds. Their strategy additionally had some assumptions that have to be examined; for instance, they assumed that the similarities of gene expression profiles examined in vitro will translate to similarities within the motion of the compounds in vivo, which could not be the case since organic programs are very advanced.
Regardless of these shortcomings, the newly recognized senotherapeutics are nice potential targets for extra detailed testing, particularly since they’ve already been underneath investigation for his or her potential anti-inflammatory, anti-cancer, and anti-aging properties.
Literature
[1] Meiners, F., Hinz, B., Boeckmann, L., Secci, R., Sueto, S., Kuepfer, L., Fuellen, G., & Barrantes, I. (2024). Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data. Scientific studies, 14(1), 6286.
[2] Bravo L. (1998). Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance.Vitamin opinions, 56(11), 317–333.
[3] Justice, J. N., Nambiar, A. M., Tchkonia, T., LeBrasseur, N. Ok., Pascual, R., Hashmi, S. Ok., Prata, L., Masternak, M. M., Kritchevsky, S. B., Musi, N., & Kirkland, J. L. (2019). Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine, 40, 554–563.
[4] Everett J. R. (2015). Academic drug discovery: current status and prospects. Expert opinion on drug discovery, 10(9), 937–944.
[5] Jarada, T. N., Rokne, J. G., & Alhajj, R. (2020). A review of computational drug repositioning: strategies, approaches, opportunities, challenges, and directions.Journal of cheminformatics, 12(1), 46.
[6] Subramanian, A., Narayan, R., Corsello, S. M., Peck, D. D., Natoli, T. E., Lu, X., Gould, J., Davis, J. F., Tubelli, A. A., Asiedu, J. Ok., Lahr, D. L., Hirschman, J. E., Liu, Z., Donahue, M., Julian, B., Khan, M., Wadden, D., Smith, I. C., Lam, D., Liberzon, A., … Golub, T. R. (2017). A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell, 171(6), 1437–1452.e17.
[7] Kung, F. P., Lim, Y. P., Chao, W. Y., Zhang, Y. S., Yu, H. I., Tai, T. S., Lu, C. H., Chen, S. H., Li, Y. Z., Zhao, P. W., Yen, Y. P., & Lee, Y. R. (2021). Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells. Cancers, 13(17), 4266.
[8] Thongsom, S., Suginta, W., Lee, Ok. J., Choe, H., & Talabnin, C. (2017). Piperlongumine induces G2/M phase arrest and apoptosis in cholangiocarcinoma cells through the ROS-JNK-ERK signaling pathway. Apoptosis : a global journal on programmed cell dying, 22(11), 1473–1484.
[9] Wang, Y., Chang, J., Liu, X., Zhang, X., Zhang, S., Zhang, X., Zhou, D., & Zheng, G. (2016). Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Getting old, 8(11), 2915–2926.
