(−)-Hinokinin Induces G2/M Arrest and Contributes to the Antiproliferative Effects of Doxorubicin in Breast Cancer Cells

Abstract

Breast cancer incidence rises worldwide and new chemotherapeutical strategies have been investigated to overcome chemoresistance. (-)-Hinokinin is a dibenzylbutyrolactone lignan derived from the partial synthesis of (-)-cubebin extracted from Piper cubeba seeds. Biological effects of dibenzylbutyrolactone lignans include antiviral, antitumor, anti-inflammatory, and trypanocidal activities. In the present study, we evaluated the ability of (-)-hinokinin to modulate the antiproliferative effects of doxorubicin intumoral (MCF-7 and SKBR-3) and normal (MCF-10 A) breast cell lines. Treatment with (-)-hinokinin did not affect the cellular proliferation or contribute to the antitproliferative effects of doxorubicin in MCF-10 A cells. After 24 and 48 hours of treatment with (-)-hinokinin, MCF-7 and SKBR-3 were accumulated in G2/M and, when combined with doxorubicin, (-)-hinokinin contributed to the antiproliferative effects of this chemotherapic by modulation of the cyclin-dependent kinase inhibitor 1. Apoptotic cell death was observed in response to (-)-hinokinin alone in MCF-7, but not in SKBR-3 even 72 hours after treatment. In MCF-7, doxorubicin-induced apoptosis was not increased by (-)-hinokinin. The findings of the present study suggest (-)-hinokinin as an antiproliferative agent that contributes to the effects of doxorubicin. (-)-Hinokinin modulates apoptotic cell death via the molecular regulation of the cell cycle and apoptotic control genes, but the cellular genetic background directly affects the cell fate decision in response to treatment.

An Ethnopharmacological, Phytochemical and Pharmacological Review on Lignans from Mexican Bursera spp.

“…Hinokinin ( 1 ) has been shown to have anti-inflammatory [ 39 , 40 , 41 , 42 ], immunosuppressive [ 43 , 44 ], antibacterial [ 45 ], and antiviral [ 46 ] properties. Hinokinin ( 1 ) was tested for several other biological activities, such as antispasmodic [ 47 ], neurite outgrowth-promoting in PC12 cells [ 48 ], antileukemic [ 49 ], antiproliferative [ 50 ], and neuroprotective activities [ 51 ]. This compound showed an interesting activity against Trypanosoma cruzi , [ 52 , 53 , 54 , 55 , 56 ], but with a low parasite selectivity [ 57 ].…”

Adenine Derivatives: Promising Candidates for Breast Cancer Treatment

“…The Sulforhodamine B assay was used to evaluate cell viability. An initial screening was performed for the compounds identified in Table , using doxorubicin as a model drug . The compounds were added to cells at two different concentrations (10 and 30 µ m ) and the effect was evaluated after 72 h of incubation (Table , Supporting Information).…”

MicroRNA‑16 sensitizes drug‑resistant breast cancer cells to Adriamycin by targeting Wip1 and Bcl‑2

“…Clinical treatment options for BC, such as surgery, radiotherapy and chemotherapy, are commonly used in clinical practice (2). As a member of the anthracycline antibiotics, Adriamycin (ADM), or doxorubicin, exerts strong antitumor effects by targeting the DNA of cancer cells, and has been widely used to treat numerous types of cancer, including BC (3–5). However, the majority of women diagnosed with advanced BC develop resistance to ADM, which limits its further application and leads to long-term chemotherapeutic resistance (6).…”