Topological properties and in vitro identification of essential nodes of the Paclitaxel and Vincristine interactomes in PC-3 cells

Abstract

BackgroundMicrotubule-targeting agents (MTAs) disrupt microtubule dynamics, thereby inducing apoptosis via mitochondrial pathway activation through the modulation in the expression of the Bcl-2 family.MethodsTo describe topological features of the MTAs networks associated to intrinsic apoptosis induction in p53-null prostate cancer cells, we predicted and compared the interactomes and topological properties of Paclitaxel and Vincristine, and thus, the essential nodes corresponding with the pro- and anti-apoptotic proteins and their kinetics were subjected to experimental analysis in PC-3 cell line.ResultsThe essential nodes of the apoptotic pathways, TP53, and CASP3, were identified in both, Paclitaxel and Vincristine networks, but the intrinsic pathway markers BCL2, BAX, and BCL2L1 were identified as hub nodes only in the Paclitaxel network. An in vitro analysis demonstrated an increase in BimEL and the cleaved-caspase-3 proteins in PC-3 cells exposed to both treatments. Immunoprecipitation analysis showed that treatments induced the releasing of Bax from the anti-apoptotic complex with Bcl-2 protein and the role of BimEL as a de-repressor from sequestering complexes, in addition, new protein complexes were identified between BimEL or Bcl-2 and cleaved-caspase-3, contributing data to the Vincristine network for p53-null cells in response to MTAs.ConclusionThe differences in sensitivities, protein profiles, and protein complex kinetics observed between the drugs confirmed that the selectivity and stimulation of the apoptotic system vary depending on the cell's genotype, the drug used and its exposure period.

Caryophyllene Oxide, the Active Compound Isolated from Leaves of Hymenaea courbaril L. (Fabaceae) with Antiproliferative and Apoptotic Effects on PC-3 Androgen-Independent Prostate Cancer Cell Line

“…Most PCs are usually acinar adenocarcinomas characterized by glandular formation, absence of basal cells, uncontrolled proliferation of tumor cells, and expression of differentiation luminal markers, such as the androgen receptor (AR) and the prostate-specific antigen (PSA), and the majority of these adenocarcinomas are androgendependent, which allows hormone therapy that inhibits AR signaling [1][2][3][4]. There are variant forms of prostatic epithelial malignancies, such as the Small-Cell Neuroendocrine Carcinoma (SCNC), which are rare tumors that account for no more than 1% of all prostate carcinomas [5,6]. They are often seen as recurrent tumors in patients who have received hormone therapy and become resistant to hormone-suppressive therapy [2,4,5].…”

“…There are variant forms of prostatic epithelial malignancies, such as the Small-Cell Neuroendocrine Carcinoma (SCNC), which are rare tumors that account for no more than 1% of all prostate carcinomas [5,6]. They are often seen as recurrent tumors in patients who have received hormone therapy and become resistant to hormone-suppressive therapy [2,4,5]. The normal prostate epithelium is constituted by luminal epithelial cells, basal cells, and a minor component of neuroendocrine (NE) cells that are scattered throughout the prostate [1,6].…”

“…High mortality rate, systemic toxicity, multidrug resistance, excessive sensitivity to conventional therapies, and the lack of specificity of synthetic drugs that display lethal effects on normal cells limit the successful results of conventional therapy, decreasing the patient's life quality [8]. Ideally, cancer therapies should have selective effects on cell destruction, requiring an urgent search for effective, targeted, and safer drugs [5]. Historically, natural products have been used since ancient times in folk medicine, with plants being a common alternative for cancer treatment in many countries, especially developing countries.…”

pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer

“…Paclitaxel (PTX) is one of these drugs commonly used as a first-line treatment of lung cancer and active against a variety of cancers. The effects of PTX mainly involve mitochondria [ 13 ] and microtubules [ 14 ] of cancer cells. Selective delivery of a drug to the mitochondria can be achieved by mitochondria-targeting signal peptides [ 15 ], oligoguanidinium [ 16 ], and triphenylphosphonium (TPP) [ 17 ] to modify drug carriers in the drug delivery systems.…”

High hopes and high honours for cancer immunotherapy

“…At the heart of this study by Delgado-Carreño and Méndez-Callejas stands the in silico identification and experimental validation of the main interactome nodes of these two drugs, with a special focus on secondary targets among the pro- and anti-apoptotic proteins [18].…”