Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism

Abstract Background: Resisting cell death is one of the hallmarks of cancer. Necroptosis is a form of non-caspase dependent necrotic cell death mediated by receptor-interacting protein kinase-1/3 (RIP1/3), which represents another mode of programmed cell death besides apoptosis. Growing evidence supports that RIP3 has emerged as a critical regulator of necroptosis and can be activated by several stimuli to trigger necroptotic cell death in a RIP1-independent manner. RIP3 also acts as an energy metabolism regulator associated with switching cell death from apoptosis to necroptosis. Natural products provide a unique source for the discovery of innovative leading compounds and drugs, which exhibits promising anticancer activities through inducing cell death and enhancing chemotherapeutic sensitivity. Trichothecin (TCN) is a sesquiterpenoid originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes and shows potent anti-tumor bioactivity. However, the underlying mechanism is not fully understood.Methods: Cell permeability assay and transmission electron microscopy were applied to identify the death pattern induced by TCN in apoptotic-resistant cancer cells. We used Seahorse extracellular flux analyzer to examine the cellular oxygen consumption rate (OCR) and flow cytometry to detect mitochondrial reactive oxygen species (ROS) content. Xenograft animal experiment was performed to assess the effect of TCN synergized with cisplatin to enhance chemotherapeutic sensitivity of tumor cells. Results: Our current findings revealed that RIP3 mediated TCN-induced necroptosis through activating mitochondria energy metabolism and ROS production in apoptotic-resistant cancer cells. RIP3 might be involved in sensitizing tumor cells to chemotherapy induced by TCN. Conclusions: Activating RIP3 to induce necroptosis through reprogramming mitochondrial energy metabolism and ROS production contributes to the anti-tumor activity of TCN. Moreover, TCN could be exploited for therapeutic gain through up-regulating RIP3 to sensitize cancer chemotherapy.

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Activation of the intrinsic-apoptotic pathway in LNCaP prostate cancer cells by genistein- topotecan combination treatments

Functional Foods in Health and Disease ◽

10.31989/ffhd.v3i3.64 ◽

2013 ◽

Vol 3 (3) ◽

pp. 66 ◽

Cited By ~ 2

Author(s):

Vanessa Hörmann ◽

Sivanesan Dhandayuthapani ◽

James Kumi-Diaka ◽

Appu Rathinavelu

Keyword(s):

Prostate Cancer ◽

Cell Death ◽

Cancer Cells ◽

Apoptotic Cell ◽

Treatment Options ◽

Attractive Alternative ◽

Intrinsic Apoptotic Pathway ◽

Prostate Cancer Cells ◽

Apoptotic Pathway ◽

Combination Treatments

Background: Prostate cancer is the second most common cancer in American men. The development of alternative preventative and/or treatment options utilizing a combination of phytochemicals and chemotherapeutic drugs could be an attractive alternative compared to conventional carcinoma treatments. Genistein isoflavone is the primary dietary phytochemical found in soy and has demonstrated anti-tumor activities in LNCaP prostate cancer cells. Topotecan Hydrochloride (Hycamtin) is an FDA-approved chemotherapy for secondary treatment of lung, ovarian and cervical cancers. The purpose of this study was to detail the potential activation of the intrinsic apoptotic pathway in LNCaP prostate cancer cells through genistein-topotecan combination treatments. Methods: LNCaP cells were cultured in complete RPMI medium in a monolayer (70-80% confluency) at 37ºC and 5% CO2. Treatment consisted of single and combination groups of genistein and topotecan for 24 hours. The treated cells were assayed for i) growth inhibition through trypan blue exclusion assay and microphotography, ii) classification of cellular death through acridine/ ethidium bromide fluorescent staining, and iii) activation of the intrinsic apoptotic pathway through Jc-1: mitochondrial membrane potential assay, cytochrome c release and Bcl-2 protein expression.Results: The overall data indicated that genistein-topotecan combination was significantly more efficacious in reducing the prostate carcinoma’s viability compared to the single treatment options. In all treatment groups, cell death occurred primarily through the activation of the intrinsic apoptotic pathway.Conclusion: The combination of topotecan and genistein has the potential to lead to treatment options with equal therapeutic efficiency as traditional chemo- and radiation therapies, but lower cell cytotoxicity and fewer side effects in patients. Key words: topotecan; genistein; intrinsic apoptotic cell death

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