Mechanism of drug-induced vacuolization in tissue culture

Yang, Wendy; Strasser, Florian; Pomerat, C. M.

doi:10.1016/0014-4827(65)90373-3

Cited by 59 publications

(33 citation statements)

References 4 publications

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“…The reasons for this discrepancy are unclear, but the difference in histological origin of the cell lines might be one. Morphological observation showed that, compared to control, 5 days of PCA treatment led to vacuolation and cell rounding in HLE cells, corresponding with a previous report [24]. In that report, Yang et al [24] stated that PCA could penetrate the cell membrane through the presence of a nonionized weak base and that this led to the induction of vacuolization.…”

Section: Discussionsupporting

confidence: 76%

“…In addition, these drugs have been shown to induce vacuoles within the cell cytoplasm [24] and interfere with intracellular microtubule function [31]. It has been reported that PCA could enhance the antitumor activity of chemotherapeutic agents such as bleomycin and cisplatin, as well as of hyperthermia [32][33][34], and this effect might be due to the above-stated property of PCA.…”

Section: Discussionmentioning

confidence: 99%

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Procaine inhibits the proliferation and DNA methylation in human hepatoma cells

et al. 2007

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Purpose Transcriptional silencing of tumor suppressor genes associated with DNA hypermethylation has been known as a hallmark of human cancer. In this study, we revealed that a local anesthetic, procaine (PCA), possessed growth-inhibitory and demethylating effect on human hepatoma cells in vitro and in vivo. Methods The viability of PCA-treated cells with or without trichostatin A (TSA) was investigated. To clarify the mechanism of the antiproliferating effect of PCA, TUNEL assay, FACS analysis, and morphological observation of PCA-treated cells were performed. The expression levels and epigenetic alterations of 4 genes inactivated by DNA hypermethylation in hepatocellular carcinoma (HCC) were examined in hepatoma cells with or without PCA treatment. The growth-inhibitory and demethylating effect of PCA in vivo was tested in nude mice bearing xenograft. Results The viability of HLE, HuH7, and HuH6 cells was significantly decreased by PCA treatment. In these cells, the combination treatment with TSA and PCA exhibited stronger reduction of the viability. Inhibition of S/G2/M transition, morphological changes such as vacuolation and no increase in apoptosis rate were observed in the PCAtreated HLE cells. All the genes transcriptionally suppressed by DNA hypermethylation were demethylated and reactivated with PCA treatment. PCA treatment led to partial demethylation and significant reduction in tumor volume in vivo. Conclusions These data indicated that PCA had growthinhibitory and demethylating effects on human hepatoma cells in vitro and in vivo. PCA may be a candidate agent for future therapies for HCC.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Procaine inhibits the proliferation and DNA methylation in human hepatoma cells

et al. 2007

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“…Although basic drugs may be trapped in a various types of acidic organelles, including mitochondria (Siebert et al, 2004), the ones that are submitted to osmotic swelling in our SMC model may originate from the trans-Golgi, on the basis of their labeling with ceramide-C5, perinuclear starting point, the presence of the vesicular ATPase sensitive to bafilomycin A1, and the absence of inhibition by the dominant negative Rab5. In previous studies, the mitochondria remained intact in hepatoma cells or fibroblasts treated with millimolar levels of procaine (Yang et al, 1965;Henics and Wheatley, 1997). It cannot been ruled out that additional organelles expressing the vacuolar ATPase and derived from the transGolgi, such as the lysosomes, also concentrate procainamide, as suggested previously for neutral red (Sousa et al, 1996).…”

Section: Discussionmentioning

confidence: 80%

“…It has been known for a long time that the formation of numerous vacuoles visible in light microscopy is a response of various types of cultured cells to some basic compounds, such as procaine, procainamide, nicotine, atropine, and many others (Belkin et al, 1962;Yang et al, 1965;Finnin et al, 1969;Ohkuma and Poole, 1981;Wheatley, 1997, 1999). This drug response transcends conventional pharmacological classes, and with the exception of local anesthetics, usually occurs at supratherapeutic concentration levels for the compounds that are used in therapeutics.…”

mentioning

confidence: 99%

Massive Cell Vacuolization Induced by Organic Amines Such as Procainamide

Morissette¹,

Moreau²,

C.‐Gaudreault³

et al. 2004

J Pharmacol Exp Ther

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Procaine and some other basic drugs reportedly induce vacuolization of various cell types. We addressed the concentrationeffect and structure-activity relationships as well as the mechanism of this effect using three cell lines. Massive vacuolization occurs over several hours in primary cultures of rabbit pulmonary artery smooth muscle cells (SMCs) and COS-1 cells in response to procaine and loosely related amine compounds (procainamide, N-acetyl-procainamide, metoclopramide, lidocaine, triethylamine, nicotine) used at 2.5 mM. Furthermore, chloroquine, propranolol, diphenhydramine, and neutral red are active in this respect at 100 to 250 M in SMCs and COS-1 cells.

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“…In early studies of lysosomal sequestration correlation was drawn between the pKa of compounds and their ability to "induce vacuolization" (Yang et al, 1965). It was well known that weak acids and bases are capable of readily diffusing lipid bilayer membranes providing pH gradients exist on either side of the membrane partition.…”

Section: Drug Sequestration Through the Endosomal Pathwaysmentioning

confidence: 99%