Potentiation of Antimetastatic Activity of Pentoxifylline in B16F10 and B16F1 Melanoma Cells Through Inhibition of Glutathione Content

Shukla, Vivek; Gude, Rajiv P.

doi:10.1089/108497803322287637

Cited by 5 publications

(6 citation statements)

References 22 publications

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“…However, this effect was more evident in the groups of cells treated with both drugs (PTX + CIS). In this regard, it was reported that PTX induces the depletion of intracellular GSH ( 27 ). It is also known that the biosynthesis of GSH is ATP-dependent.…”

Section: Discussionmentioning

confidence: 99%

Pentoxifylline Sensitizes Cisplatin-Resistant Human Cervical Cancer Cells to Cisplatin Treatment: Involvement of Mitochondrial and NF-Kappa B Pathways

et al. 2020

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BackgroundCervical cancer continues to be a major public health problem worldwide, and Cisplatin is used as first-line chemotherapy for this cancer; however, malignant cells exposed to CISplatin (CIS) become insensitive to the effects of this drug. PenToXifylline (PTX) is a xanthine that sensitizes several types of tumor cells to apoptosis induced by antitumor drugs, such as Adriamycin, Carboplatin, and CIS. The effects of PTX on tumor cells have been related to the disruption of the NF-κB pathway, thus preventing the activation of cell survival mechanisms such as the expression of anti-apoptotic genes, the secretion of proinflammatory interleukins, and growth factors.ObjectiveIn this work, we studied the antitumor proprieties of PTX in human SiHa cervical carcinoma cells resistant to CIS.Materials and MethodsSiHa and HeLa cervical cancer cells and their CIS-resistant derived cell lines (SiHaCIS-R and HeLaCIS-R, respectively) were used as in-vitro models. We studied the effects of PTX alone or in combination with CIS on cell viability, apoptosis, caspase-3, caspase-8, and caspase-9 activity, cleaved PARP-1, anti-apoptotic protein (Bcl-2 and Bcl-xL) levels, p65 phosphorylation, cadmium chloride (CdCl2) sensitivity, Platinum (Pt) accumulation, and glutathione (GSH) levels, as well as on the gene expression of GSH and drug transporters (influx and efflux).ResultsPTX sensitized SiHaCIS-R cells to the effects of CIS by inducing apoptosis, caspase activation, and PARP-1 cleavage. PTX treatment also decreased p65 phosphorylation, increased Pt levels, depleted GSH, and downregulated the expression of the ATP7A, ATP7B, GSR, and MGST1 genes.ConclusionPTX reverses the acquired phenotype of CIS resistance close to the sensitivity of parental SiHa cells.

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Section: Discussionmentioning

confidence: 99%

Pentoxifylline Sensitizes Cisplatin-Resistant Human Cervical Cancer Cells to Cisplatin Treatment: Involvement of Mitochondrial and NF-Kappa B Pathways

et al. 2020

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“…Pentoxifylline, the next compound selected in our study, is clinically used in patients with chronic peripheral arterial disease to increase blood flow and to enhance tissue oxygenation. In melanoma cell lines, pentoxifylline combined with irradiation significantly increased radiotoxicity in a TP53 mutant cell line, effectively suppressed DNA double-strand break repair [46], inhibited in G 1 -S phase transition [47], caused glutathione depletion and increased glutathione-S-transferase activity [48]. In in vivo experiments, it showed anti-metastatic activity [49], and significantly inhibited subcutaneous melanoma xenograft growth and angiogenesis without any toxicity [50], [51].…”

Section: Discussionmentioning

confidence: 99%

Natural Compounds' Activity against Cancer Stem-Like or Fast-Cycling Melanoma Cells

et al. 2014

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BackgroundAccumulating evidence supports the concept that melanoma is highly heterogeneous and sustained by a small subpopulation of melanoma stem-like cells. Those cells are considered as responsible for tumor resistance to therapies. Moreover, melanoma cells are characterized by their high phenotypic plasticity. Consequently, both melanoma stem-like cells and their more differentiated progeny must be eradicated to achieve durable cure. By reevaluating compounds in heterogeneous melanoma populations, it might be possible to select compounds with activity not only against fast-cycling cells but also against cancer stem-like cells. Natural compounds were the focus of the present study.MethodsWe analyzed 120 compounds from The Natural Products Set II to identify compounds active against melanoma populations grown in an anchorage-independent manner and enriched with cells exerting self-renewing capacity. Cell viability, cell cycle arrest, apoptosis, gene expression, clonogenic survival and label-retention were analyzed.FindingsSeveral compounds efficiently eradicated cells with clonogenic capacity and nanaomycin A, streptonigrin and toyocamycin were effective at 0.1 µM. Other anti-clonogenic but not highly cytotoxic compounds such as bryostatin 1, siomycin A, illudin M, michellamine B and pentoxifylline markedly reduced the frequency of ABCB5 (ATP-binding cassette, sub-family B, member 5)-positive cells. On the contrary, treatment with maytansine and colchicine selected for cells expressing this transporter. Maytansine, streptonigrin, toyocamycin and colchicine, even if highly cytotoxic, left a small subpopulation of slow-dividing cells unaffected. Compounds selected in the present study differentially altered the expression of melanocyte/melanoma specific microphthalmia-associated transcription factor (MITF) and proto-oncogene c-MYC.ConclusionSelected anti-clonogenic compounds might be further investigated as potential adjuvants targeting melanoma stem-like cells in the combined anti-melanoma therapy, whereas selected cytotoxic but not anti-clonogenic compounds, which increased the frequency of ABCB5-positive cells and remained slow-cycling cells unaffected, might be considered as a tool to enrich cultures with cells exhibiting melanoma stem cell characteristics.

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“…We further studied the intracellular degradability of DDMONs–PEI, DMONs–PEI, and MONs–PEI after incubation with HEK293t normal cells and B16 melanoma cancer cells (B16F0). It was reported that the intracellular GSH levels in B16 melanoma could reach 30–40 nmol/10 6 cells, , while the intracellular GSH levels in HEK293 cells were only around 12.4 ± 0.39 nmol/10 6 cells . These data suggest that the B16 cancer cells have ∼threefold higher GSH than HEK293 normal cells.…”

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confidence: 99%

Structure-Dependent and Glutathione-Responsive Biodegradable Dendritic Mesoporous Organosilica Nanoparticles for Safe Protein Delivery

et al. 2016

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The design of smart nanocarriers that could recognize and differentiate cancer cells and normal cells is of great importance in drug delivery. Here we report the first example of cancer cell-specific degradable dendritic mesoporous organosilica nanoparticles (DDMONs). A unique pore structure-dependent glutathione (GSH)responsive degradation behavior is revealed: the degradation rates of two nanoparticles with different pore sizes are similar in normal cells ("leveling effect"), while large-pore DDMONs show a faster degradation rate than small-pore nanoparticles in cancer cells with relatively high intracellular GSH levels ("differentiating effect"). The cancer cell-specific degradability and concomitant cargo release lead to efficient protein delivery toward cancer cells but reduced cytotoxicity toward normal cells.

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Potentiation of Antimetastatic Activity of Pentoxifylline in B16F10 and B16F1 Melanoma Cells Through Inhibition of Glutathione Content

Abstract: Pentoxifylline, an effective membrane modifier, showed significant depletion in glutathione level in conjunction with increased lipid peroxidation. The results suggested an antimetastatic property by PTX at a nontoxic dose in B16F10 and B16F1 melanoma cells.

Cited by 5 publications

References 22 publications

Pentoxifylline Sensitizes Cisplatin-Resistant Human Cervical Cancer Cells to Cisplatin Treatment: Involvement of Mitochondrial and NF-Kappa B Pathways

Pentoxifylline Sensitizes Cisplatin-Resistant Human Cervical Cancer Cells to Cisplatin Treatment: Involvement of Mitochondrial and NF-Kappa B Pathways

Natural Compounds' Activity against Cancer Stem-Like or Fast-Cycling Melanoma Cells

Structure-Dependent and Glutathione-Responsive Biodegradable Dendritic Mesoporous Organosilica Nanoparticles for Safe Protein Delivery

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