Bioactivity Studies of Hesperidin and XAV939

Abstract

The present work aimed to evaluate the reactivity of natural bioflavonoid hesperidin (HSP) and synthetically derived XAV939 (XAV) against human hepatocellular carcinoma (HepG2), human breast cancer (MDA-MB231) cancer cell lines, and related molecular and pathological profiles. Data recorded revealed that the cytotoxic potential of the tested products was found to be cell type-and concentration-dependent. The halfmaximal inhibitory concentration (IC 50 ) value of the HSP-XAV mixture against MDA-MB231 was significantly decreased in the case of using the HSP-XAV mixture against the HepG2 cell line. Also, there was a significant upregulation of the phosphotumor suppressor protein gene (P53) and proapoptotic genes such as B-cell lymphomaassociated X-protein (Bax, CK, and Caspase-3), while antiapoptotic gene B-cell lymphoma (Bcl-2) was significantly downregulated compared with the untreated cell control. The cell cycle analysis demonstrated that DNA accumulation was detected mainly during the G2/ M phase of the cell cycle accompanied with the elevated reactive oxygen species level in the treatment of HepG2 and MDA-MB231 cell lines by the HSP-XAV mixture, more significantly than that in the case of cell control. Finally, our finding suggests that both HSP and XAV939 and their mixture may offer an alternative in human liver and breast cancer therapy.

Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer

“…A similar synergy was also observed when XAV939 was used in conjunction with (i) GW843682X, a polo-like kinase 1 inhibitor, in MDA-MB-468 and BT-549 triple-negative breast cancer cell lines; (ii) palbociclib, a United States Food and Drug Administration (FDA)-approved inhibitor of cyclin-dependent kinases 4 and 6 (CDKs 4/6), in DLD-1 cells; (iii) U0126, a m itogen-activated protein kinase/ e xtracellular signal-regulated kinase k inase (MEK) inhibitor, or MK-2206, an AKT inhibitor, in HLE and SNU-449 HCC cell lines; (iv) BX795 or Ro-31–8220, two nonselective inhibitors of extracellular signal-regulated kinase 8, in HeLa cells . Plausible molecular mechanisms underlying those synergistic effects either remain to be determined (i) or involve downregulation of the WNT/β-catenin (ii) or Hippo (iii) pathway or modulation of telomerase activity (iv). − More recently, the combination of XAV939 with hesperetin (the aglycone form of a naturally occurring flavanone glycoside called hesperidin) gave rise to synergetic effects on both HepG2 human HCC and MDA-MB-231 cell lines …”

“…121−123 More recently, the combination of XAV939 with hesperetin (the aglycone form of a naturally occurring flavanone glycoside called hesperidin) gave rise to synergetic effects on both HepG2 human HCC and MDA-MB-231 cell lines. 124 In addition to in vitro cytotoxicity and mechanism-of-action studies, the anticancer efficacy of XAV939 has been assessed in vivo. As a single agent, XAV939 inhibited the growth of subcutaneous HepG2 xenografts in mice (at 20 mg/kg every three days for three weeks via an intratumor injection due to the hydrophobic nature of the molecule), and no significant changes in body weight were observed.…”

Naringenin and Hesperidin as Promising Alternatives for Prevention and Co-Adjuvant Therapy for Breast Cancer

“…In addition, the treatment increased RS levels, accompanied by higher DNA accumulation during the G2/M phase in both cell lines. According to the results, the authors suggest that the synergism promoted between HSP and XAV may be promising as an alternative in the therapy of human liver and breast cancer [ 131 ].…”