Enhancement of Anti-metastatic Activity of Pentoxifylline by Encapsulation in Conventional Liposomes and Sterically Stabilized Liposomes in Murine Experimental B16F10 Melanoma Model

Sant, Vinayak; Nagarsenker, Mangal S.; Rao, Shaline; Gude, Rajiv P.

doi:10.1211/0022357001777667

Cited by 12 publications

(4 citation statements)

References 21 publications

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“…18) In the present study, the NF-κB inhibitors PTX, NAC, and ASP showed protective effects in our in vivo lung metastasis model. PTX, widely used as a hemorheological agent in the treatment of peripheral vascular disease, was earlier shown to suppress lung metastasis formation by B16F10 melanoma 19,20) and NAC, a chemopreventive agent that acts through a variety of mechanisms, 21) inhibits VEGF production in human melanoma cell lines, 22) invasion of endothelial cells, 23) and invasion of human bladder cancer cells through the suppression of MMP-9. 24) ASP has been demonstrated to inhibit angiogenesis, 25) invasion and metastasis of EBV-associated tumors, 26) and HGF-induced invasiveness of HepG2 human hepatoma cells.…”

Section: Discussionmentioning

confidence: 99%

Suppression of metastasis by nuclear factor kB inhibitors in an in vivo lung metastasis model of chemically induced hepatocellular carcinoma

Futakuchi¹,

Ogawa²,

Tamano³

et al. 2004

Cancer Science

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To evaluate the suppressive effects of nuclear factor kappa B (NF-κ κ κ κB) inhibitors on metastasis, three agents, pentoxifylline (PTX, 0.5% in diet), N-acetyl-L-cysteine (NAC, 0.5% in diet), and aspirin (ASP, 0.5% in diet) were applied in an in vivo highly metastatic rat hepatocellular carcinoma (HCC) model in F344 male rats. Administration of NF-κ κ κ κB inhibitors for 8 weeks after induction of highly metastatic HCC by sequential treatment with diethylnitrosamine and N-nitrosomorpholine did not cause any significant change in survival rate or body weight. The incidence of HCC was 100% at week 23, regardless of treatment with NF-κ κ κ κB inhibitors. PTX, NAC, and ASP did not exert any significant effect on the development or differentiation of HCCs, although PTX tended to decrease the multiplicity of HCC. Although no lung metastasis was observed in the rats killed at the end of the period of carcinogen exposure, lung metastasis was found in 100% of animals in all the groups at the end of the experiment. Multiplicity of lung metastasis was significantly decreased by PTX and NAC, whereas ASP was without significant influence. The size of metastatic nodules was also significantly reduced in the PTX treatment group. Furthermore, the inhibitory κ κ κ κ-B (Iκ κ κ κB) protein level, considered to be a marker for the degree of NF-κ κ κ κB transcription, was significantly suppressed by PTX. mRNA expression in HCC for vascular cell adhesion molecule-1 (VCAM-1), which is considered to play a key role in attachment of cancer cells to the endothelium, was significantly suppressed by PTX. Among the splicing variants of VEGF, VEGF-A120, VEGF-A144, VEGF-A164, and VEGF-A188, suppressed mRNA expression of VEGF-A188 appeared to be correlated with suppression of lung metastasis formation. In conclusion, the present study demonstrated that NF-κ κ κ κB inhibitors have the potential to inhibit lung metastasis from rat HCCs in vivo, and PTX is especially promising. Its mechanism of action may involve suppression of VCAM-1 and VEGF-A188 production. Our previous study demonstrated that aspirin (ASP) has the potential to inhibit lung metastasis by rat HCCs in vivo, although the observed suppressive effect was marginal.2) The mechanism appeared to involve a decrease in the intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which play important roles in attachment of tumor cells to the vascular endothelium. 2)Induction of ICAM-1 and VCAM-1 is mediated by the transcription factor nuclear factor-kappa B (NF-κB) [3][4][5][6] and ASP has been shown to inhibit NF-κB-dependent transcription weakly.7) Therefore, a stronger inhibitor of NF-κB might be expected to have a stronger inhibitory effect on lung metastasis formation.In order to evaluate the suppressive effects of NF-κB inhibitors, we examined three examples, pentoxifylline (PTX), 8,9) Nacetyl-L-cysteine (NAC), 10,11) and ASP, 7) in our in vivo lung metastasis model. To evaluate the degree of inhibition of NF-κB transcription, inhibitor of κB (IκB)...

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Section: Discussionmentioning

confidence: 99%

Suppression of metastasis by nuclear factor kB inhibitors in an in vivo lung metastasis model of chemically induced hepatocellular carcinoma

Futakuchi¹,

Ogawa²,

Tamano³

et al. 2004

Cancer Science

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“…The pretreatment method describes the situation in which a patient is detected with primary tumor and receives chemotherapy, while the post-treatment method entails a situation in which metastasis has already been detected and then chemotherapy has started. Furthermore, liposomal pentoxifyline and niosomal cisplatin demonstrated higher antimetastatic activity compared with plain drug, indicating the usefulness of nanocarrier in treatment of metastasis (Gude et al 2002 ; Sant et al 2000 ). The market-available DOXIL® (pegylated doxorubicin liposomes) which is used in metastasis was not that much defined by clinical trials due to a poor understanding of its role in the prevention of metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…C57BL/6 mice were injected with 0.1 million B16F10 cells in 0.1 ml of PBS through intravenous route by the tail vein (Sant et al 2000 ). One group received only B16F10 cells and served as a control.…”

Section: Methodsmentioning

confidence: 99%

EILDV-conjugated, etoposide-loaded biodegradable polymeric micelles directing to tumor metastatic cells overexpressing α4β1 integrin

et al. 2011

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In the present study, poly(ethylene glycol)-b-poly(ε-caprolactone) micelles loaded with etoposide (ETO) were formulated and further conjugated with pentapeptide Glu-Ile-Leu-Asp-Val (EILDV) to target α4β1 integrin receptor overexpressed on metastatic tumor cell. Using a distinct ratio of carboxyl-terminated poly(ethylene glycol)-block-poly(ε-caprolactone) (HOOC–PEG-b-PCL) to methoxy-poly(ethylene glycol)-block-poly(ε-caprolactone (CH3O–PEG-b-PCL) polymers, we formulated a series of micellar formulations having different surface densities of EILDV and observed optimum cellular uptake of micelles with 10% EILDV surface density by B16F10 cells. The cytotoxicity of EILDV-conjugated micelles was observed close to 1.5-fold higher than plain ETO after 72 h of drug incubation, demonstrating controlled release of drug inside the cell after enhanced intracellular uptake with the ability to selectively target cancer cells. In addition, EILDV-conjugated micelles inhibited the migration of B16F10 cells effectively compared with plain ETO and non-conjugated micellar formulations when cells were treated with equivalent cytotoxic concentration of the drug, i.e., IC25. B16F10 cells treated with EILDV-conjugated micelles showed a significant reduction in the attachment of cells to the substrate-coated plate compared with non-conjugated micellar formulations, implying retention of the biological activity of EILDV after coupling to micelles. Furthermore, the in vivo experimental metastasis assay conducted on C57BL/6 mice demonstrated significant activity of EIDLV-conjugated micelles in the reduction of pulmonary metastatic nodule formation in both pretreatment and post-treatment methods. In conclusion, EIDLV-conjugated micelles showed higher efficacy in the treatment of metastasis and would be a promising approach in the treatment of metastasis.

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“…PTX, widely used as a hemorheological agent in the treatment of peripheral vascular disease, was earlier shown to suppress lung metastasis formation by B16F10 melanoma [43] and NAC inhibits VEGF production in human melanoma cell lines [44], invasion of endothelial cells [45], and invasion of human bladder cancer cells through the suppression of MMP-9 [46]. ASP has been demonstrated to inhibit angiogenesis [47] and HGF-induced invasiveness of HepG2 human hepatoma cells [48].…”

Section: Suppression Of Metastasis By Nuclear Factor Kappab Inhibitormentioning

confidence: 99%

Animal Model of Lung Metastasis of Hepatocellular Carcinoma: A Tool for the Development of Anti-Metastatic Therapeutics

Futakuchi¹

2013

JCT

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We observed that N-nitrosomorpholine (NMOR) given after a multi-carcinogenic treatment induced liver carcinomas with 56% lung metastasis. An additional treatment with diethylnitrosamine (DEN) with NMOR further enhanced the incidence of hepatocellular carcinoma (HCC) with lung metastasis. We have further revised the duration of NMOR treatment to establish an animal model with a simple experimental protocol and an appropriate experimental duration to facilitate investigation exploring the mechanisms of HCC metastasis and development of anti-metastatic therapeutics. We observed that DEN exposure followed by a 16-week treatment with NMOR to be a most efficient protocol for the induction of HCC metastasizing to the lung. In this review, we will discuss about the usefulness of animal models for induction of highly metastatic HCC and the assessment of the efficacy of anti-metastatic therapeutics. Additionally, we will also discuss use of these models in analysis of individual steps in the metastatic process by using non-steroidal anti-inflammatory drugs, aspirin and indomethacin, two nuclear factor kappa B (NF-κB) inhibitors, pentoxifylline and N-acetyl-L-cysteine.

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Enhancement of Anti-metastatic Activity of Pentoxifylline by Encapsulation in Conventional Liposomes and Sterically Stabilized Liposomes in Murine Experimental B16F10 Melanoma Model

Cited by 12 publications

References 21 publications

Suppression of metastasis by nuclear factor kB inhibitors in an in vivo lung metastasis model of chemically induced hepatocellular carcinoma

Suppression of metastasis by nuclear factor kB inhibitors in an in vivo lung metastasis model of chemically induced hepatocellular carcinoma

EILDV-conjugated, etoposide-loaded biodegradable polymeric micelles directing to tumor metastatic cells overexpressing α4β1 integrin

Animal Model of Lung Metastasis of Hepatocellular Carcinoma: A Tool for the Development of Anti-Metastatic Therapeutics

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