Retinoic Acids in the Treatment of Most Lethal Solid Cancers

Abstract

Although the use of oral administration of pharmacological all-trans retinoic acid (ATRA) concentration in acute promyelocytic leukaemia (APL) patients was approved for over 20 years and used as standard therapy still to date, the same use in solid cancers is still controversial. In the present review the literature about the top five lethal solid cancers (lung, stomach, liver, breast, and colon cancer), as defined by The Global Cancer Observatory of World Health Organization, and retinoic acids (ATRA, 9-cis retinoic acid, and 13-cis retinoic acid, RA) was compared. The action of retinoic acids in inhibiting the cell proliferation was found in several cell pathways and compartments: from membrane and cytoplasmic signaling, to metabolic enzymes, to gene expression. However, in parallel in the most aggressive phenotypes several escape routes have evolved conferring retinoic acids-resistance. The comparison between different solid cancer types pointed out that for some cancer types several information are still lacking. Moreover, even though some pathways and escape routes are the same between the cancer types, sometimes they can differently respond to retinoic acid therapy, so that generalization cannot be made. Further studies on molecular pathways are needed to perform combinatorial trials that allow overcoming retinoic acids resistance.

Docosahexaenoic Acid Reverted the All-trans Retinoic Acid-Induced Cellular Proliferation of T24 Bladder Cancer Cell Line

“…Instead, among the up regulated proteins, beyond those implicated in the metabolism of proteins and in the post-translation protein modifications, obviously necessary to proliferation, others involved in the regulation of IGF transport and uptake by IGFBPs, and in the RAF/MAP kinase cascade were found. IGF exerts a pro-survival action stimulating the PI3k/Akt pathway, and other evidence in the literature showed that in ATRA-sensitive cancer cells, ATRA suppresses IGFs proliferative action, whilst in ATRA-resistant cell lines the IGFs proliferative action occurs for several modified molecular mechanism [4]. In support of this data, previous papers showed the up regulation of the IGFs proliferation pathway in T24 cells in comparison to normal urothelial cells [17,18].…”

“…Similarly, also proteins of the RAF/MAP kinase pathway turned out to be up-regulated following ATRA treatment in T24 cells. Also in this case, RAF/MAP kinase pathway is inhibited by ATRA treatment in ATRA-sensitive cells, but in ATRA-resistant this pathway is functional and through c-jun and c-fos lead to cellular proliferation [4]. However, the molecular mechanisms by which ATRA up or down regulated the described pathways in T24 cells need to be investigated.…”

“…Indeed, it is well known that in the treatment of solid cancers the ATRA action is questionable. Although, ATRA can inhibit cancer cell proliferation at different levels, from membrane to gene expression, in parallel the cancer cells have evolved several escape routes to bypass these ATRA actions, developing ATRA-resistance [4]. In some cases, molecular pathways deregulations reverse the ATRA action from the growth inhibitory/differentiating to the anti-apoptotic/proliferative action.…”

“…However, it was shown that some solid cancers activate a non-genomic pathway due to less CRABP-II concentration in comparison to another retinol-binding protein, FABP5. In these cases, FABP5 delivered ATRA to the nuclear PPARβ/δ stimulating cellular proliferation [4,7]. Although few papers showed that the maintenance treatment of APL with ATRA is not associated with higher incidence of secondary cancers, it is worth noting that long-term follow-up studies that analyze the APL maintenance therapy adverse effects are actually limited and/or examined a very limited statistical population [8,9].…”

Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ

“…In combination with chemotherapy or arsenic trioxide, ATRA is used in the treatment of acute promyelocytic leukemia with outstanding results, inducing long-term remission in the majority of patients [ 14 ]. The therapeutic activity observed in this type of acute leukemia has raised interest in the use of ATRA and derived synthetic retinoids for the personalized management of solid tumors, including breast cancer [ 15 ]. In this last context, a substantial number of pre-clinical in vitro and in vivo results indicate that ATRA is a promising agent in the treatment/chemo-prevention of mammary tumors [ 12 , 16 ].…”