Page 28 - TD-2-2

Tumor Discovery A comprehensive review of bexarotene

peroxisome proliferator-activated receptors (PPARs), and (C max ) and the area under the plasma concentration-time
thyroid hormone receptor (TR), ultimately leading to curve (AUC) escalated with an increase in the dose .
[9]
transcriptional changes in the tumor cell .
[4]
Bexarotene exerts its biological effects through selective 3. Mechanism of action
binding and activation of RXR subtypes, including RXRα, Bexarotene acts as an agonist for RXRs, specifically RXRα,
RXRβ, and RXRγ . Unlike other synthetic retinoids, RXRβ, and RXRγ. RXRs are nuclear receptors that form
[5]
bexarotene has demonstrated effectiveness at all stages heterodimers with other nuclear receptors, such as RARs
of CTCL. In this article, we have articulated the utility of and TRs. Activation of RXRs by bexarotene can lead to
bexarotene in treating multiform disease, its formulation changes in gene expression, resulting in anti-tumor effects.
development, various patents, and the need for future Bexarotene also interacts with PPARs, specifically PPARγ.
research to explore its clinical potential in treating PPARs are transcription factors that regulate various cellular
aggressive carcinomas. processes, including lipid metabolism, inflammation, and
cell proliferation. Activation of PPARγ by bexarotene has
2. Hurdles in the formulation development been implicated in the inhibition of tumor growth and
of bexarotene differentiation of cancer cells. Bexarotene can interact with
RARs, which are nuclear receptors that bind retinoic acid.
Bexarotene is a solid, fine white powder with a molar mass However, the affinity of bexarotene for RARs is relatively
of 348.478 g/mol and the chemical formula C H O . low compared to its affinity for RXRs. The exact role of
24
2
28
Chemically, it is known as 4-(1-(5,6,7,8-tetrahydro-3,5,5,8,8- RAR interaction in the therapeutic effects of bexarotene
pentamethyl-2-naphthalen-yl)ethenyl) benzoic acid. The is not fully understood. Bexarotene has been shown to
structural formula of bexarotene is depicted in Figure 1. modulate lipid metabolism by activating certain genes
Bexarotene falls under the biopharmaceutical involved in lipid homeostasis [10,11] .
classification system class-ІІ, indicating that it is sparingly Bexarotene exerts its pharmacological effects through
soluble in water. However, with slight warming, it has the selective activation of RXRs and subsequent modulation
demonstrated solubility of 65 mg/mL in dimethylsulfoxide of gene expression . In addition, its interaction with
[11]
and 10 mg/mL in ethanol. Low aqueous solubility and PPARγ and its potential influence on lipid metabolism
low bioavailability are hurdles that make it arduous to contribute to its therapeutic properties. The primary
develop an appropriate formulation of this drug and have, mechanism of action of bexarotene is believed to be its
consequently, limited its clinical usage . The partition selective activation of RXRs, which are nuclear receptors
[6]
coefficient (log P) and dissociation constant (pK ) of involved in regulating gene expression, as illustrated in
a
bexarotene are 6.9 and 4.07, respectively. It is considered a Figure 2. Some key aspects of the mechanism of action of
strong acid and has a melting point of 230 – 231°C . The bexarotene are further elaborated below.
[7]
λ max of this drug is reported to be 264 nm .
[8]
Bexarotene is available in oral and topical dosage forms. 3.1. Activation of RXRs
It was inferred that about 54% of CTCL patients responded Bexarotene acts as a potent agonist for RXRs, specifically
to oral bexarotene at the dose of 300 mg/m /day, whereas RXRα, RXRβ, and RXRγ subtypes. Upon binding to these
2
the level of response was increased to 63% after using receptors, bexarotene induces conformational changes,
0.1 – 1% bexarotene topically daily in CTCL patients . leading to the formation of heterodimer complexes with
[3]
Pronounced inter- and intra-patient variations were other nuclear receptors, such as RARs. These activated RXR
observed in the concentration of bexarotene in plasma heterodimers can then bind to specific DNA sequences
at all dosage levels when administered to 27 patients known as retinoic acid response elements (RAREs) within
with various malignancies (doses ranging from 5 to target gene promoters .
[11]
400 mg/m /day). The mean peak plasma concentration
2
3.2. Modulation of gene expression
The RXR heterodimers formed by bexarotene binding
have the ability to recruit co-activator or co-repressor
proteins to the target gene promoters. This recruitment
can lead to either the enhancement or suppression of
gene transcription, resulting in the modulation of various
biological processes. The specific genes and pathways
influenced by bexarotene can vary depending on the cell
[11]
Figure 1. Structure of bexarotene. type and context .

Volume 2 Issue 2 (2023) 2 https://doi.org/10.36922/td.0436