Sodium 4-Carboxymethoxyimino-(4-HPR) a Novel Water-Soluble Derivative of 4-Oxo-4-HPR Endowed with In Vivo Anticancer Activity on Solid Tumors

Our plain-English summary of Sodium 4-Carboxymethoxyimino-(4-HPR) a Novel Water-Soluble Derivative of 4-Oxo-4-HPR Endowed with In Vivo Anticancer Activity on Solid Tumors, by P. Tiberio, E. Cavadini, L. Cleris, et al (Frontiers in Pharmacology, 2017).

The study

• Authors: P. Tiberio, E. Cavadini, L. Cleris, S. Dallavalle, L. Musso, M.G. Daidone, V. Appierto
• Journal: Frontiers in Pharmacology
• Published: 2017;8:226
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), an active polar metabolite of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR), was shown to exert promising antitumor activity through at least two independent mechanisms of action. Specifically, differently from 4-HPR and other retinoids, 4-oxo-4-HPR targets microtubules and inhibits tubulin polymerization causing mitotic arrest and on the other hand, analogously to the parent drug, it induces apoptosis through the activation of a signaling cascade involving the generation of reactive oxygen species (ROS). However, the potential in vivo use of 4-oxo-4-HPR is impaired by its poor solubility. By chemical modification of 4-oxo-4-HPR, a new class of compounds with improved solubility and in vivo bioavailability was obtained. We demonstrated here that, among them, the most promising molecule, sodium 4-carboxymethoxyimino-(4-HPR), was endowed with in vitro antitumor efficacy and entirely preserved the double mechanism of action of the parent drug in cancer cells of different histotypes. In fact, the retinoid induced the activation of the apoptotic cascade related to the generation of ROS through endoplasmic reticulum stress response and upregulation of phospho c-Jun N-terminal kinases and PLAcental Bone morphogenetic protein, leading to cell death through caspase-3 cleavage. Otherwise, sodium 4-carboxymethoxyimino-(4-HPR) caused a marked mitotic arrest coupled with multipolar spindle formation and tubulin depolymerization. To assess the compound antitumor activity, in vivo experiments were performed in three mouse xenograft models (ovarian and breast cancers and mesothelioma). The in vivo results demonstrated that retinoid administration as single agent significantly increased the survival in ovarian cancer xenografts, induced a statistically significant decrease in tumor growth in breast cancer xenografts, and caused a 30% reduction in tumor growth in a mesothelioma mouse model. Even though further studies investigating sodium 4-carboxymethoxyimino-(4-HPR) toxicity and in vitro and in vivo activities in combination with other drugs are required, the double mechanism of action of the retinoid coupled with its in vivo antitumor efficacy and potential low toxicity suggest a promising therapeutic potential for the compound in different solid tumors.

In plain English

This laboratory and animal study, from a cancer institute in Milan, Italy, tested an experimental drug, sodium 4-carboxymethoxyimino-(4-HPR), a water-soluble derivative of a synthetic retinoid. It did not study asbestos exposure. In cell cultures the drug inhibited the growth of human ovarian, breast, neuroblastoma and mesothelioma cell lines. For the two mesothelioma lines, STO and MESO, which came from patients' surgical specimens, the 50% effective concentrations were 1.48 and 1.28 µM. In STO cells and other lines, the drug caused signs of cell death and stopped cells at the dividing stage. In mice carrying human tumors, it significantly increased survival in an ovarian cancer model (p < 0.01 at 60 and 90 mg/kg) and significantly reduced breast tumor growth (p = 0.01). In the peritoneal mesothelioma model (STO cells), tumor growth was reduced by about 30%, but this was not statistically significant. The authors noted high variability in how these tumors grew. Body weight loss was at most 9%. The authors concluded the drug had antitumor activity in different solid tumors but said further toxicity and combination studies are required.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study on human cancer cell lines plus animal experiments in mice carrying transplanted human tumors (xenografts)
• Who was studied: Eleven human cancer cell lines (ovarian, breast, neuroblastoma, and two mesothelioma lines, STO and MESO, established by the authors' group from surgical specimens of patients at the Istituto Nazionale dei Tumori, Milan). Also nude mice and NOD/SCID mice given human peritoneal mesothelioma (STO), ovarian carcinoma (IGROV-1) or breast cancer (MDA-MB-231) cells. The number of mice per group is not stated, except for six additional mice in the ovarian model.
• Exposure: No asbestos exposure was studied. The exposure was the experimental drug sodium 4-carboxymethoxyimino-(4-HPR): 0.3 to 10 µM in cell cultures. In the mesothelioma mice it was given at 30 and 60 mg/kg by injection into the abdomen, 5 days/week for 5 weeks. Ovarian mice received 30, 60 and 90 mg/kg for 3 weeks, and breast cancer mice 90 mg/kg, 4 days/week for 7 weeks.
• Main results:
  • In cell cultures, the 50% effective concentration (EC50) was 1.48 µM for the STO mesothelioma line and 1.28 µM for the MESO mesothelioma line. The other lines ranged from 1.3 µM (neuroblastoma) to 5.96 µM (ovarian).
  • In STO mesothelioma, IGROV-1 ovarian and MDA-MB-231 breast cancer cells, the drug induced PLAB upregulation and caspase-3 cleavage (markers of the cell-death pathway) and a marked G2-M cell cycle arrest.
  • In A2780 ovarian cells, adding vitamin C blocked the drug's generation of reactive oxygen species. It did not prevent the mitotic arrest or abnormal spindles, which the authors interpreted as a separate, independent mechanism.
  • In mice with mesothelioma (STO) xenografts, treatment reduced tumor growth at both doses, but statistical significance was not reached.
  • The reduction in tumor growth in the mesothelioma mouse model was 30%.
  • In mice with IGROV-1 ovarian cancer, doses of 60 and 90 mg/kg significantly increased survival.
  • In the ovarian model, three treated mice (60 mg/kg) were compared with three control mice. Solid tumor mass was reduced by 62% (on average 0.59 g in controls vs 0.22 g in treated mice) and the number of ascitic cells by 90%.
  • In mice with MDA-MB-231 triple negative breast cancer, 90 mg/kg significantly reduced tumor growth.
  • Across all mouse experiments, maximum body weight loss was 9%, limited to the first 3 days of treatment.
• The authors' conclusion: The authors concluded that the drug has antitumor activity in cell cultures and in mice in different solid tumors. They said further studies of its toxicity and of its use in combination with other drugs are required to know whether it has actual therapeutic potential.
• Limitations the authors state:
  • The STO mesothelioma xenografts showed high variability in tumor growth, which the authors said plausibly affected the test of statistical significance.
  • Tolerability (toxicity) experiments have not yet been done. The low toxicity is an expectation based on related compounds and preliminary observations.
  • Further studies of toxicity and of combinations with other drugs are needed to know whether the compound has actual therapeutic potential.

Topics

Medical terms in this study, explained in our Lexicon: Apoptosis, Reactive Oxygen Species (ROS), Mesothelioma, Ovarian Cancer.

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