Dual control of Shuanghuang Shengbai granule on upstream and downstream signal modulators of CyclinD-CDK4/6 signaling pathway of cell cycle in Lewis-bearing mice with cyclophosphamide-induced myelosuppression

Abstract

BackgroundThis study investigated the dual control mechanism of the Shuanghuang Shengbai granule in modulating the cell cycle in Lewis-bearing mice with cyclophosphamide induced myelosuppression.MethodsThirty Lewis-bearing mice were randomly grouped into an untreated group, control group, and treated group. Both treated and untreated groups were intraperitoneally injected with cyclophosphamide to produce a myelosuppression model. Mice in the treated group were fed with the Shuanghuang Shengbai granule (40 g/day) for 6 consecutive days. Standard blood tests and the count of bone marrow nuclear cells were performed, and the cell reproductive cycles of bone marrow and tumors were measured in these mice. In addition, the western blot approach was used to measure the upstream activating signals of CyclinD-CDK4/6 such as c-Myc and CDC25A, the upstream suppression signals such as p16INK4a, and the expression of downstream activated signals such as Rb, pRB, and E2F. All of the tested results were validated by reverse transcription quantitative real-time polymerase chain reaction.ResultsThe results showed that the Shuanghuang Shengbai granule could elevate the count of leukocyte and bone marrow nuclear cells of Lewis-bearing mice with cyclophosphamide induced myelosuppression. It could also stimulate bone marrow cells to move from G0/G1 phases to S phase, accelerating the progress of the cell reproductive cycle and increasing the cell proliferation index. Simultaneously, the Shuanghuang Shengbai granule could also suppress cancer cells moving from G0/G1 phase to S phase, reducing the proliferation index. The tumor weight of Lewis-bearing mice in the treated group was much less than those of the control group. Expression levels of c-Myc, CDC25A, Rb, pRb, and E2F of bone marrow in Shuanghuang Shengbai granule-treated mice was higher compared to the control group, whereas they were lower in the cancer cells.ConclusionThe experimental results demonstrate that the Shuanghuang Shengbai granule has dual control on the cell reproductive cycles in cancer cells and bone marrow nuclear cells in Lewis-bearing mice.

[6]‐Gingerol enhances the cisplatin sensitivity of gastric cancer cells through inhibition of proliferation and invasion via PI3K/AKT signaling pathway

“…Cyclin D binds with and activates CDK4/CDK6, forming cyclin-CDK complex, and then activates the following cyclin E/cyclin A2dependent CDK2, followed by phosphorylation of Rb protein, thus driving cell transition from G1 to S phase (Gu et al, 2013). P21 and P27 are negative cell cycle regulators.…”

ZhenQi FuZheng Formula Improves Mouse Hematopoietic Function after Cyclophosphamide-Induced Damage via Enhancing Macrophage Colony-Stimulating Factor Concentrations

“…In the clinic, the injection of recombinant human granulocyte colony-stimulating factor (rhG-CSF) is commonly used to treat myelosuppression and can prevent chemotherapy-induced neutropenia and enhance the function of mature neutrophils [13]. However, adverse effects of rhG-CSF have been noted, such as the proliferation of cancer cells [14].…”

Shuanghuang Shengbai granule cures myelosuppression and suppresses lung cancer progression: mechanism and therapeutic targets from the aspect of microRNAs

“…However, these drugs can lead to lung injury, splenic rupture and vascular events, and they even promote cancer development and metastasis [ 8 , 9 ]. As a traditional Chinese medicine, Shuanghuang Shengbai (SHSB) granule has been widely used in clinic for decades in China [ 10 ]. It can increase white blood cells (WBCs) and cure myelosuppression, whereas it cannot cause obvious adverse effect or cancer progression [ 11 , 12 ].…”

“…SHSB granule can reduce the percentage of bone marrow cells (BMCs) in G0/G1 phase and increase the proliferation index of BMCs via up-regulating CDK4, CDK6 and cyclin D1 [ 15 ]. Also, it promotes the transformation of hematopoietic stem cells from G0/G1 phase to S phase via up-regulating c-Myc, cell division cycle 25A, Rb, pRb and E2F in bone marrow nuclear cells [ 10 ]. On the contrary, it inhibits the proliferation of tumor cells in an opposite way [ 10 , 15 ].…”

“…Also, it promotes the transformation of hematopoietic stem cells from G0/G1 phase to S phase via up-regulating c-Myc, cell division cycle 25A, Rb, pRb and E2F in bone marrow nuclear cells [ 10 ]. On the contrary, it inhibits the proliferation of tumor cells in an opposite way [ 10 , 15 ].…”