Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

Abstract

Abstract. For proper determination of the apoptotic potential of chemoxenobiotics in synergism, it is important to understand the modes, levels and character of interactions of chemoxenobiotics with cells in the context of predicted conserved biophysical properties. Chemoxenobiotic structures are studied with respect to atom distribution over molecular space, the predicted overall octanol-to-water partition coefficient (Log OWPC; unitless) and molecular size viz a viz van der Waals diameter (vdWD). The Log OWPC-to-vdWD (nm -1 ) parameter is determined, and where applicable, hydrophilic interacting moiety/core-to-vdWD (nm -1 ) and lipophilic incorporating hydrophobic moiety/core-to-vdWD (nm -1 ) parameters of their part-structures are determined. The cellular and sub-cellular level interactions of the spectrum of xenobiotic chemotherapies have been characterized, for which a classification system has been developed based on predicted conserved biophysical properties with respect to the mode of chemotherapeutic effect. The findings of this study are applicable towards improving the effectiveness of existing combination chemotherapy regimens and the predictive accuracy of personalized cancer treatment algorithms as well as towards the selection of appropriate novel xenobiotics with the potential to be potent chemotherapeutics for dendrimer nanoparticle-based effective transvascular delivery. IntroductionSmall molecules non-endogenous to the biological system, often referred to as xenobiotics, include a diverse variety of molecules, simple organic toxicants with uncomplicated structures and natural eukaryotic antibiotics and synthetic molecules of more complicated structures and cytotoxic properties (1), the latter of which have chemotherapeutic properties. Although small molecule chemoxenobiotics, of various traditional classes, form the basis of present synergistic cancer treatment strategies, their clinical efficacy remains questionable for the treatment of solid and hematopoietic malignancies alike, upon surgical resection in the former, and during bone marrow irradiation-transplantation and after in the latter. For this reason, a better understanding of the modes and character underlying molecular cellular interactions is necessary, particularly for the purposes of improving the tumor tissue selectiveness of enhanced permeation and retention (EPR)-based chemotherapy (2), which has a prolonged blood half-life but is non-selective for solid tumor foci. Along these lines, there has been relatively recent translational advancement towards the development of optimally sized dendrimer nanoparticle-based small molecule chemotherapy at ~9 nm (H D ) (3-7), which selectively delivers small molecule chemoxenobiotics into solid malignancies at effective concentrations without systemic toxicity (4,8). As such, with optimally sized dendrimer nanoparticle-based small molecule chemotherapy, there is the potential for complete tumor regression (3,9) in lieu of the possibility for the development of drug resistance phenotypes (1...

Pressure regulated basis for gene transcription by delta-cell micro-compliance modeled in silico: Biphenyl, bisphenol and small molecule ligand models of cell contraction-expansion

“…Furthermore, since the Δ C micro contraction-expansion interface for the co-, ortho-planar PCB pathway is within the 0.140 (Gft2ird1) -0.149 (Cyp4a11) P eff interval, there is an inactivation of gene TFF1 (pS2, P eff 0.147) with applied co-, ortho-planar PCB-104 [108]. Thus, when paraquat, a weakly intracellularly-localizing endocytic agent with 1+ IS/SS 1+ ionicity at the lower limit of cationicity [109], results in a (+) P eff Δ C micro contraction-expansion response when it is applied in a PCB model (co-, or ortho-) [110], it potentiates a convergent oxidative stress pathway with gene re-activation.…”

Inhibition of bcl-2 and cox-2 Protein Expression after Local Application of a New Carmustine-Loaded Clinoptilolite-Based Delivery System in a Chemically Induced Skin Cancer Model in Mice

“…Therefore, clinoptilolite is able to act as a molecular sieve. Because carmustine is a small-molecular chemotherapeutic agent (its molecular size resulted from the predicted spherical van der Waals volume being of 4.8 Å [ 31 ]), its molecule size is compatible with the A channels aperture of the clinoptilolite framework, formed by 10-membered rings (3.0 × 7.6 Å).…”