Naturally Occurring Bicoumarin Compound Daphnoretin Inhibits Growth and Induces Megakaryocytic Differentiation in Human Chronic Myeloid Leukemia Cells

Abstract

Daphnoretin extracted from the stem and roots of Wikstroemia indica (L.) C.A. Mey has been shown to possess antiviral and antitumor activities. Herein, we hypothesized that daphnoretin might induce megakaryocytic differentiation, thereby inhibiting the proliferation of cells and serving as a differentiation therapy agent for chronic myeloid leukemia (CML). Daphnoretin-treated K562 and HEL cells were examined for growth inhibition, cell morphology, and megakaryocyte-specific markers. Potential mechanisms of megakaryocytic differentiation of daphnoretin-treated K562 cells were evaluated. The results showed that daphnoretin inhibited the growth of K562 and HEL cells in a dose- and time-dependent manner. Flow cytometry analyses revealed that daphnoretin treatment slightly increased the proportion of sub-G1 and polyploid cells compared to that of dimethyl sulfoxide (DMSO)-treated control cells. Morphological examination showed that daphnoretin-treated K562 and HEL cells exhibited enlarged contours and multinucleation as megakaryocytic characteristics compared to DMSO-treated control cells. Daphnoretin treatment also dramatically enhanced the expression of megakaryocytic markers CD61 and CD41. Under optimal megakaryocytic differentiation conditions, daphnoretin increased the phosphorylation of STAT3 but not STAT5. In summary, daphnoretin inhibited cell growth and induced megakaryocytic differentiation in K562 and HEL cells. The efficacy of daphnoretin in vivo and in patients with CML may need further investigations for validation.

Identification of Daphnane Diterpenoids from Wikstroemia indica Using Liquid Chromatography with Tandem Mass Spectrometry

“…Importantly, all these peaks were subsequently confirmed to be present in the crude diterpenoid fraction through extracted ion chromatogram (XIC) analysis (Figure 1, Table 1). 793 (36), 775 (22), 765 (19), 747 (20), 731 (34), 703 (23), 689 (16), 671 (47), 659 (12), 653 (17), 643 (17), 625 (24), 609 (18), 567 (24), 549 (100), 531 (15), 521 (39), 507 (36), 503 (37), 493 (10), 489 (66), 479 (18), 477 (18), 471 (37), 461 (68), 459 (23), 443 (80), 433 (24), 431 (25), 425 (23), 415 (31), 403 (27), 397 (19), 375 (22), 363 (18), 339 (23), 325 (16), 307 (37), 295 (22), 291 (21), 279 (37), 263 (22), 221 (21), 183 (18), 181 (47), 153 (16), 141 (25)…”

“…, 461 (66), 451 (53), 449 (25), 443 (20), 433 (59),425 (24), 423 (13), 421 (16), 415 (21), 407 (14), 405 (21), 403 (16), 309 (14), 291 (12), 281 (13), 263 (12), 211 (13), 187 (19), 185 (16), 159 (13), 135 (13), 133 (27) pimelea factor S 6 [ (21), 599 (22), 545 (63), 527 (33), 495 (47), 477 (85), 459 (100), 449 (21), 447 (28), 441 (37), 431 (50), 429 (20), 423 (90), 419 (18), 413 (29), 405 (24), 401 (23), 319 (18), 309 (24), 291 (24), 281 (18), 279 (23), 263 (19), 251 (18), 151 (27)…”

“…is a semi-evergreen shrub mainly distributed in southeastern China, which has long been used as a traditional Chinese medicine for the treatment of bronchitis, hepatitis, and cancer [21]. Recent studies have revealed that the extract of this plant exhibited antiallergic [22], anti-inflammatory [23], and antineoplastic properties [24], therefore heightening interest in its pharmacological exploration. While previous phytochemical investigations of W. indica have yielded coumarins [25], flavonoids [26], lignans [27], and sesquiterpenoids [28], the presence of daphnane diterpenoids has yet to be documented.…”

Prospects of Computer-Aided Molecular Design of Coumarins as Ecotoxicologically Safe Plant Protection Agents

“…Depending on the substitution of the 1-benzopyran-2-one skeleton, coumarins can be divided into several types: simple coumarins, furanocoumarins, pyranocoumarins, and other coumarins (Figure 1). This great structural diversity of these natural compounds and their synthesized derivatives enables their wide range of pharmacological activities, such as antioxidant [8][9][10]; antibacterial [11][12][13][14][15][16][17]; antifungal [18][19][20]; anti-human immunodeficiency virus (HIV) infection [21,22]; anti-tubercular [23]; cytotoxicity [24]; and anti-cancer activities [25][26][27][28][29]. There are also many reports about their effectiveness against plant pathogenic pests.…”

Advances in Plants-Derived Bioactives for Cancer Treatment

“…The work by Cuciniello et al [ 8 ] addressed the anticancer effects of aglianico grape seed semi-polar extract in mesothelioma cell lines. Specifically, in this work, the authors stated, through transcriptomic and metabolomic analyses, that the extract exerted a pronounced pro-apoptotic effect by modulating murine double minute 2 (MDM2) expression and ultimately inhibiting tumor progression.…”