Local application of γ-linolenic acid in the treatment of human gliomas

Das, Undurti N.; Prasad, Vannemreddy; Reddy, D.R

doi:10.1016/0304-3835(95)03844-m

Cited by 109 publications

(54 citation statements)

References 19 publications

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“…Particularly promising therapeutic effects were obtained with the administration of GLA directly into the tumour cavity in patients with malignant glioblastomas and astrocytomas (Das et al, 1995). The tumours regressed and survival was substantially prolonged.…”

Section: Introductionmentioning

confidence: 99%

In vivo and in vitro biotransformation of the lithium salt of gamma-linolenic acid by three human carcinomas

Antueno¹,

Elliot²,

Ells³

et al. 1997

Br J Cancer

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Summary Lipid metabolism has been considered recently as a novel target for cancer therapy. In this field, lithium gamma-linolenate (LiGLA) is a promising experimental compound for use in the treatment of human tumours. In. vivo and in vitro studies allowed us to assess the metabolism of radiolabelled LiGLA by tumour tissue and different organs of the host. In vitro studies demonstrated that human pancreatic (AsPC-1), prostatic (PC-3) and mammary carcinoma (ZR-75-1) cells were capable of elongating GLA from LiGLA to dihomo-gamma-linolenic acid (DGLA) and further desaturating it to arachidonic acid (AA). AsPC-1 cells showed the lowest A5-desaturase activity on DGLA. In the in vivo studies, nude mice bearing the human carcinomas were given Li[1-14C]GLA (2.5 mg kg-') by intravenous injection for 30 min. Mice were either sacrificed after infusion or left for up to 96 h recovery before sacrifice. In general, the organs showed a maximum uptake of radioactivity 30 min after the infusion started (t = 0). Thereafter, in major organs the percentage of injected radioactivity per g of tissue declined below 1% 96 h after infusion. In kidney, brain, testes/ovaries and all three tumour tissues, labelling remained constant throughout the experiment. The ratio of radioactivity in liver to tumour tissues ranged between 16-and 24-fold at t = 0 and between 3.1-and 3.7-fold at 96 h. All tissues showed a progressive increase in the proportion of radioactivity associated with AA with a concomitant decrease in radiolabelled GLA as the time after infusion increased. DGLA declined rapidly in liver and plasma, but at a much slower rate in brain and malignant tissue. Seventy-two hours after the infusion, GLA was only detected in plasma and tumour tissue. The sum of GLA + DGLA varied among tumour tissues, but it remained 2-4 times higher than in liver and plasma. In brain, DGLA is the major contributor to the sum of these fatty acids. Data showed that cytotoxic GLA and DGLA, the latter provided either by the host or by endogenous synthesis, remained in human tumours for at least 4 days.

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Section: Introductionmentioning

confidence: 99%

In vivo and in vitro biotransformation of the lithium salt of gamma-linolenic acid by three human carcinomas

Antueno¹,

Elliot²,

Ells³

et al. 1997

Br J Cancer

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“…4 -6 More recently, pilot clinical trials of GLA have achieved useful tumour regression and improved quality of life with negligible systemic toxicity in a variety of advanced solid malignancies. [7][8][9][10] GLA and other EFAs have been shown to enhance the in vitro anti-cancer actions of radiotherapy and of cytotoxic drugs and may have beneficial role in the reversal of multi-drug resistance. 3 In the current work the effects of GLA combined with an endocrine agent in a hormonally responsive cancer have been explored.…”

mentioning

confidence: 99%

Effect of dietary GLA+/?tamoxifen on the growth, ER expression and fatty acid profile of ER positive human breast cancer xenografts

et al. 2001

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“…In addition, clinical studies show that intracerebral injection of ␥-linolenic acid in patients with gliomas induces decreased tumor size (12,13). Moreover, earlier studies had also shown that injection of LA and ␣-linolenic acid increases survival of rats with Mat 1376 ascites tumors (11).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo intratumoral injection of PUFAs induces tumor regression (8 -10) and improves survival (11). Moreover, clinical studies have shown that intratumoral injection of PUFAs in patients with intractable gliomas improves survival and induces partial tumor regression without causing side effects (12,13).…”

mentioning

confidence: 99%

Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic Acid

Comba

Almada

Tolosa

et al. 2016

Journal of Biological Chemistry

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Numerous reports have demonstrated a tumor inhibitory effect of polyunsaturated fatty acids (PUFAs). However, the molecular mechanisms modulating this phenomenon are in part poorly understood. Here, we provide evidence of a novel antitumoral mechanism of the PUFA arachidonic acid (AA). In vivo and in vitro experiments showed that AA treatment decreased tumor growth and metastasis and increased apoptosis. Molecular analysis of this effect showed significantly reduced expression of a subset of antiapoptotic proteins, including BCL2, BFL1/A1, and 4-1BB, in AA-treated cells. We demonstrated that down-regulation of the transcription factor gliomaassociated protein 1 (GLI1) in AA-treated cells is the underlying mechanism controlling BCL2, BFL1/A1, and 4-1BB expression. Using luciferase reporters, chromatin immunoprecipitation, and expression studies, we found that GLI1 binds to the promoter of these antiapoptotic molecules and regulates their expression and promoter activity. We provide evidence that AA-induced apoptosis and down-regulation of antiapoptotic genes can be inhibited by overexpressing GLI1 in AA-sensitive cells. Conversely, inhibition of GLI1 mimics AA treatments, leading to decreased tumor growth, cell viability, and expression of antiapoptotic molecules. Further characterization showed that AA represses GLI1 expression by stimulating nuclear translocation of NFATc1, which then binds the GLI1 promoter and represses its transcription. AA was shown to increase reactive oxygen species. Treatment with antioxidants impaired the AAinduced apoptosis and down-regulation of GLI1 and NFATc1 activation, indicating that NFATc1 activation and GLI1 repression require the generation of reactive oxygen species. Collectively, these results define a novel mechanism underlying AA antitumoral functions that may serve as a foundation for future PUFA-based therapeutic approaches.

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Local application of γ-linolenic acid in the treatment of human gliomas

Cited by 109 publications

References 19 publications

In vivo and in vitro biotransformation of the lithium salt of gamma-linolenic acid by three human carcinomas

In vivo and in vitro biotransformation of the lithium salt of gamma-linolenic acid by three human carcinomas

Effect of dietary GLA+/?tamoxifen on the growth, ER expression and fatty acid profile of ER positive human breast cancer xenografts

Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic Acid

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