Synergistic effect of co-treatment with all-trans retinoic acid and 9-cis retinoic acid on human lung cancer cell line at molecular level

Published on Tuesday, 30 April 2019

Abstract

The major challenge in treating cancers with ATRA is the limited availability inside the cell and resistance developed in prolonged treatment.

We made an attempt for co-treatment of human NSCLC cell lines (A549) with ATRA and its isomeric precursor (9cisRA).

In this study, the growth inhibitory effect of ATRA, 9cisRA and combination of both were tested in A549 cells by MTT and Trypan blue assays.

As the effects of retinoid are mediated through their receptors, their gene expression levels were analyzed by RT-PCR. The target gene receptor, RAR-β protein expression, was analyzed by immunocytochemistry.

The cancer cell (A549) growth inhibitory effect was significantly (p ≤ 0.001) enhanced in combination treatment when compared with the result of individual treatments.

The mRNA expression levels of both RAR-β and RXR-β were found to be increased in co-treatment (band density of 0.75 and 0.806, respectively) when compared with 9cisRA treatment (0.25 and 0.112) and ATRA treatment (0.01 and 0.081).

A concomitant enhancement in the target RAR-β protein expression was observed in co-treated cells when compared with individual treatments.

We thus conclude that the co-treatment had increased the availability of ATRA, by isomerization of the 9cisRA which then resulted in an increased expression of both RAR-β and RXR-β receptors and the target protein RAR-β which in turn inhibited lung cancer cell growth.

Our study results have explored the mechanism of synergistic effect of co-treatment with ATRA and 9cisRA and further preclinical studies are necessary to validate the application of co-treatment of retinoid in clinical use.

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About this publication.

- All-Trans-Retinoic Acid (ATRA - analogues and/or derivatives) - In vitro, review and in vivo publications;

- The Di Bella Method (A Fixed Part - All-Trans Retinoic Acid, Analogues and/or Derivatives - Approximately 60mg per day orally: 40mg per day Beta-Carotene/β-Carotene, 10mg per day ATRA and 10mg per day Axerophthol palmitate);

- Solution of retinoids in vitamin E in the Di Bella Method biological multitherapy;

- The Di Bella Method (A Fixed Part - Alpha tocopheryl acetate/Vitamin E, approximately 20 grams per day orally);

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;

- Observations on the Report of a case of pulmonary adenocarcinoma with lymph node, hepatic and osseus metastasis;

- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide;