Abstract
ObjectiveThe aim of the present study was to examine the apoptosis-promoting effects and mechanisms of hematoporphyrin monomethyl ether (HMME)-sonodynamic therapy (SDT) on endometrial cancer cells in vitro.MethodsEndometrial cancer cell samples were divided into four groups: 1) untreated control group, 2) HMME group, 3) pure ultrasound group, and 4) HMME combined with ultrasound, i.e. SDT group. CCK-8 method was utilized to assess the inhibiting effect of SDT on the proliferation of endometrial cancer cells. Optical microscope and field emission transmission electron microscopy were used to characterize the morphology changes of the cancer cells induced by the treatments. Apoptosis rate, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were examined by flow cytometer. Fluorescence intensity measured by laser scanning confocal microscopy was used to explore the variation of intracellular calcium ion (Ca2+) concentration. Apoptosis-related proteins involved in both intrinsic and extrinsic apoptosis signallings were analyzed by western blot.ResultsSDT can effectively induce the apoptosis of endometrial cancer cells. Compared with ultrasound which is known as an effective anti-tumor method, SDT leads to a significant improvement on suppression of cell viability and induction of apoptosis, together with more remarkable modifications on the morphology and substructure in both ultrasound sensitive and resistant endometrial cancer cells. Further studies reveals that SDT promotes ROS production, induces loss of MMP and increases intracellular Ca2+ concentration more efficiently than HMME or ultrasound alone. SDT groups also show a rather high expression of apoptosis-promoting proteins, including Bax, Fas and Fas-L, and a significant low expression of apoptosis-suspending proteins including Bcl-2 and Survivin. Meanwhile, both cleaved caspse-3 and caspase-8 are dramatically enhanced in SDT groups. Multiple pathways has been proposed in the process, including the intrinsic activation by excessive ROS and overloaded Ca2+, silencing survivin gene, and the extrinsic pathway mediated by the death receptor.ConclusionGiven its considerable effectivity in both ultrasound sensitive and resistant cells, SDT may therefore be a promising therapeutic method for treating endometrial cancers.
Highlights
Endometrial cancer is one of common gynecological malignancies, traditionally treated by surgery and supplemented by chemotherapy and radiotherapy, which have a rather low sensitivity to early or metastatic stage of endometrial cancer, normally accompanying with significant side-effects [1,2]
sonodynamic therapy (SDT) can effectively induce the apoptosis of endometrial cancer cells
Compared with ultrasound which is known as an effective anti-tumor method, SDT leads to a significant improvement on suppression of cell viability and induction of apoptosis, together with more remarkable modifications on the morphology and substructure in both ultrasound sensitive
Summary
Endometrial cancer is one of common gynecological malignancies, traditionally treated by surgery and supplemented by chemotherapy and radiotherapy, which have a rather low sensitivity to early or metastatic stage of endometrial cancer, normally accompanying with significant side-effects [1,2]. It is still an open issue how early endometrial cancer can be treated while preserving fertility. HMME has a much higher uptake rate by tumor than normal tissues [10], and this high selectivity ensures the ultrasound energy to be focused on the cancer cells
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