Sodium 4-carboxymethoxyimino-(4-HPR) a novel water-soluble derivative of 4-Oxo-4-HPR endowed with in vivo anticancer activity on solid tumors

Paola Tiberio, Elena Cavadini, Loredana Cleris, Sabrina Dallavalle, Loana Musso, Maria G. Daidone, Valentina Appierto

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Article number226
JournalFrontiers in Pharmacology
Volume8
Issue numberAPR
DOIs
Publication statusPublished - Apr 26 2017

Fingerprint

Fenretinide
Retinoids
Sodium
Heterografts
Water
Mesothelioma
Neoplasms
Tubulin
Ovarian Neoplasms
Solubility
Reactive Oxygen Species
Pharmaceutical Preparations
Breast Neoplasms
Pregnancy Proteins
Bone Morphogenetic Proteins
Endoplasmic Reticulum Stress
JNK Mitogen-Activated Protein Kinases
Growth
Microtubules
Caspase 3

Keywords

  • Antimitotic agent
  • Apoptosis
  • Retinoids
  • ROS
  • Sodium 4-carboxymethoxyimino-(4-HPR)
  • Solid tumors
  • Tubulin

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Sodium 4-carboxymethoxyimino-(4-HPR) a novel water-soluble derivative of 4-Oxo-4-HPR endowed with in vivo anticancer activity on solid tumors. / Tiberio, Paola; Cavadini, Elena; Cleris, Loredana; Dallavalle, Sabrina; Musso, Loana; Daidone, Maria G.; Appierto, Valentina.

In: Frontiers in Pharmacology, Vol. 8, No. APR, 226, 26.04.2017.

Research output: Contribution to journalArticle

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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.",
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