Study of the mechanisms of crocetin‐induced differentiation and apoptosis in human acute promyelocytic leukemia cells

Abstract

Crocetin, the major carotenoid in saffron, exhibits potent anticancer effects. However, the antileukemic effects of crocetin are still unclear, especially in primary acute promyelocytic leukemia (APL) cells. In the current study, the potential antipromyelocytic leukemia activity of crocetin and the underlying molecular mechanisms were investigated. Crocetin (100 µM), like standard anti-APL drugs, all-trans retinoic acid (ATRA, 10 µM) and As O (arsenic trioxide, 50 µM), significantly inhibited proliferation and induced apoptosis in primary APL cells, as well as NB4 and HL60 cells. The effect was associated with the decreased expressions of prosurvival genes Akt and BCL2, the multidrug resistance (MDR) proteins, ABCB1 and ABCC1 and the inhibition of tyrosyl-DNA phosphodiesterase 1 (TDP1), while the expressions of proapoptotic genes CASP3, CASP9, and BAX/BCL2 ratio were significantly increased. In contrast, crocetin at relatively low concentration (10 µM), like ATRA (1 µM) and As O (0.5 µM), induced differentiation of leukemic cells toward granulocytic pattern, and increased the number of differentiated cells expressing CD11b and CD14, while the number of the immature cells expressing CD34 or CD33 was decreased. Furthermore, crocetin suppressed the expression of clinical marker promyelocytic leukemia/retinoic acid receptor-α ( PML/RARα) in NB4 and primary APL cells, and reduced the expression of histone deacetylase 1 ( HDAC1) in all leukemic cells. The results suggested that crocetin can be considered as a candidate for future preclinical and clinical trials of complementary APL treatment.

Crocetin Extracted from Saffron Shows Antitumor Effects in Models of Human Glioblastoma

“…These results, which were in line with the microscopic considerations, suggested that attempted transitions from mesenchymal to neuronal lineage occurred in the GBM cells exposed to crocetin treatment. Different independent studies showed the capacity of crocetin to induce cancer cell differentiation through the inhibition of particular factors involved in the regulation of gene expression, such as HDACs [33,34]. Indeed, these proteins are important players in the onset and maintenance of tumors due to their inhibitory effects on the expression of suppressor genes in neoplastic disease.…”

Therapeutic Potential of Certain Terpenoids as Anticancer Agents: A Scoping Review

“…Artesunate & Artemisinin , β-Elemene [138,139] Diterpenoids Triptolide [140][141][142][143][144][145][146][147][148][149][150][151][152][153][154], Crocetin [155][156][157][158][159][160][161][162][163][164][165], Phytol [166][167][168] Triterpenoids Ursolic acid [169][170][171][172][173][174][175][176][177][178][179][180], Betulinic acid [181][182][183][184][185][186][187]…”

“…Another study also reported that crocetin arrests KYSE-150 cells at the S phase, alters cell morphology and enhances the expression of Bax, and caspases apoptotic genes [158]. The anticancer molecular mechanism of crocetin in primary APL cells, HL60 cells and NB4 cells via the inhibition of pro-survival genes, such as Akt and Bcl-2, multidrug-resistant proteins (ABCB1 and ABCC1) and tyrosyl-DNA phosphodiesterase 1 (TDP1), as well as the overexpression of pro-apoptotic genes, such as caspase 3, 9 and Bax [159]. The tumor preventive effects of crocetin on N-methyl-N nitrosourea (NMU)-induced breast cancer in rats was also examined, where the inhibitory molecular mechanism triggered alterations in Bax and Bcl-2 expression levels, caspase activation, cell cycle arrest via cyclin D1, p21, and p53 modulation and interaction with DNA sequence [160].…”

Differentiation-Inducing Activity of the Phyto-polyphenols Epigallocatechin-3-gallate and Kaempferol on NB4 Cells

“…The lysates were examined for the protein expression of acetyl-H3K4, which was detailed in ref. (24).…”