METHODS: In the present studies, the consequence of PPARβ/δ inhibition either by global genetic deletion or by a specific PPARβ/δ antagonist, 10h, on malignant transformation of melanoma cells and melanoma metastasis was examined using both in vitro and in vivo models.
RESULTS: Our study showed that 10h promotes epithelial-mesenchymal transition (EMT), migration, adhesion, invasion and trans-endothelial migration of mouse melanoma B16/F10 cells. We further demonstrated an increased tumour cell extravasation in the lungs of wild-type mice subjected to 10h treatment and in Pparβ/δ-/- mice in an experimental mouse model of blood-borne pulmonary metastasis by tail vein injection. This observation was further supported by an increased tumour burden in the lungs of Pparβ/δ-/- mice as demonstrated in the same animal model.
CONCLUSION: These results indicated a protective role of PPARβ/δ in melanoma progression and metastasis.
AREAS COVERED: We discuss improved understanding of the concept of drug resistance, the basis of continuous therapy, intermittent clinical regimens, and adaptive therapy will be reviewed. In addition, we discuss how adaptive therapy provides guidance for future cancer treatment.
EXPERT OPINION: The current understanding of drug resistance in cancer leads to poor prognosis and limited treatment options in patients. Fighting drug resistance mutants is constantly followed by new forms of resistance. In most reported cases, continuous therapy leads to drug resistance and an intermittent clinical regimen vaguely delays it. However, adaptive therapy, conceptually, exploits multiple parameters that can suppress the growth of drug resistance and provides safe treatment for cancer patients in the future.
AIM OF THE STUDY: This study aimed to evaluate the protective anti-inflammatory potential and better understand the underlying mechanism of action of APEE50 in a clinically-relevant mouse asthma model. Thereafter, develop the ethanolic extract of AP as a supplement for asthma prophylaxis.
MATERIALS AND METHOD: APEE50 was prepared and standardized for AGP, NAG, and DDAG using a high-performance liquid chromatography system. Asthma was induced according to a 14-day house dust mite (HDM) induction protocol. The prophylactic potential of APEE50 (50 mg/kg - 200 mg/kg) was determined by assessing cardinal asthma features, which included BALF leukocyte and differential cell count, BALF cytokine assay, histology, gene expression, and airway hyperreactivity study.
RESULTS: APEE50 significantly inhibited HDM-induced airway eosinophilia and neutrophilia. In addition to decreased levels of IL-4, IL-5, IL-13, and eotaxin in bronchoalveolar fluid, APEE50 abrogated HDM-induced airway mucus over-secretion and airway hyper-responsiveness. Administration of APEE50 downregulated HDM-induced upregulation of the oxidative stress enzyme Duox1 (dual oxidase 1) and marginally induced Nfe2l2 (nuclear factor erythroid 2-related factor 2) gene expressions. Similarly, Th2-related (Serpinb2, Clca3a1, Il4 and Il13) and Muc5ac gene expression were significantly downregulated.
CONCLUSION: Prophylactic administration of APEE50 prevented the progression of HDM-induced asthmatic responses by down-regulating Th2 cytokine gene expression and oxidative stress level.