The recent development of high throughput compound screening has allowed drug repurposing to emerge as an effective avenue for discovering novel treatments for cancer. FDA-approved antipsychotic ...drugs fluspirilene, penfluridol, and pimozide are clinically used for the treatment of psychotic disorders, primarily schizophrenia. These compounds, belong to diphenylbutylpiperidine class of antipsychotic drugs, are the potent inhibitors of dopamine D2 receptor and calcium channel. A correlation has been found that patients treated for schizophrenia have lower incidences of certain types of cancer, such as respiratory, prostate, and bladder cancers. These compounds have also been shown to inhibit cancer proliferation in a variety of cancer cells, including melanoma, lung carcinoma, breast cancer, pancreatic cancer, glioma, and prostate cancer, among others. Antipsychotic drugs induce apoptosis and suppress metastasis in in vitro and in vivo models through mechanisms involving p53, STAT3, STAT5, protein phosphatase 2A, cholesterol homeostasis, integrins, autophagy, USP1, wnt/β-catenin signaling, and DNA repair. Additionally, pre-clinical evidence suggests that penfluridol and pimozide act synergistically with existing chemotherapeutic agents, such as dasatinib, temozolomide, and cisplatin. Some studies have also reported that the cytotoxic activity of the antipsychotics is selective for dividing cells. Based on this growing body of evidence and the availability and previous FDA-approval of the drugs, the compounds appear to be promising anti-cancer agents.
Role of Phytochemicals in Cancer Prevention Ranjan, Alok; Ramachandran, Sharavan; Gupta, Nehal ...
International journal of molecular sciences,
10/2019, Letnik:
20, Številka:
20
Journal Article
Recenzirano
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The use of synthetic, natural, or biological agents to minimize the occurrence of cancer in healthy individuals is defined as cancer chemoprevention. Chemopreventive agents inhibit the development of ...cancer either by impeding DNA damage, which leads to malignancy or by reversing or blocking the division of premalignant cells with DNA damage. The benefit of this approach has been demonstrated in clinical trials of breast, prostate, and colon cancer. The continuous increase in cancer cases, failure of conventional chemotherapies to control cancer, and excessive toxicity of chemotherapies clearly demand an alternative approach. The first trial to show benefit of chemoprevention was undertaken in breast cancer patients with the use of tamoxifen, which demonstrated a significant decrease in invasive breast cancer. The success of using chemopreventive agents for protecting the high risk populations from cancer indicates that the strategy is rational and promising. Dietary components such as capsaicin, cucurbitacin B, isoflavones, catechins, lycopenes, benzyl isothiocyanate, phenethyl isothiocyanate, and piperlongumine have demonstrated inhibitory effects on cancer cells indicating that they may serve as chemopreventive agents. In this review, we have addressed the mechanism of chemopreventive and anticancer effects of several natural agents.
Immune checkpoint proteins (ICP) are currently one of the most novel and promising areas of immune-oncology research. This novel way of targeting tumor cells has shown favorable success over the past ...few years with some FDA approvals such as Ipilimumab, Nivolumab, Pembrolizumab etc. Currently, more than 3000 clinical trials of immunotherapeutic agents are ongoing with majority being ICPs. However, as the number of trials increase so do the challenges. Some challenges such as adverse side effects, non-specific binding on healthy tissues and absence of response in some subset populations are critical obstacles. For a safe and effective further therapeutic development of molecules targeting ICPs, understanding their mechanism at molecular level is crucial. Since ICPs are mostly membrane bound receptors, a number of downstream signaling pathways divaricate following ligand-receptor binding. Most ICPs are expressed on more than one type of immune cell populations. Further, the expression varies within a cell type. This naturally varied expression pattern adds to the difficulty of targeting specific effector immune cell types against cancer. Hence, understanding the expression pattern and cellular mechanism helps lay out the possible effect of any immunotherapy. In this review, we discuss the signaling mechanism, expression pattern among various immune cells and molecular interactions derived using interaction database analysis (BioGRID).
HER2 is an oncogene, expression of which leads to poor prognosis in 30% of breast cancer patients. Although trastuzumab is apparently an effective therapy against HER2-positive tumors, its systemic ...toxicity and resistance in the majority of patients restricts its applicability. In this study we evaluated the effects of phenethyl isothiocyanate (PEITC) in HER2-positive breast cancer cells.
MDA-MB-231 and MCF-7 breast cancer cells stably transfected with HER2 (high HER2 (HH)) were used in this study. The effect of PEITC was evaluated using cytotoxicity and apoptosis assay in these syngeneic cells. Western blotting was used to delineate HER2 signaling. SCID/NOD mice were implanted with MDA-MB-231 (HH) xenografts.
Our results show that treatment of MDA-MB-231 and MCF-7 cells with varying concentrations of PEITC for 24 h extensively reduced the survival of the cells with a 50% inhibitory concentration (IC50) of 8 μM in MDA-MB-231 and 14 μM in MCF-7 cells. PEITC treatment substantially decreased the expression of HER2, epidermal growth factor receptor (EGFR) and phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr-705. The expression of BCL-2-associated × (BAX) and BIM proteins were increased, whereas the levels of B cell lymphoma-extra large (BCL-XL) and X-linked inhibitor of apoptosis protein (XIAP) were significantly decreased in both the cell lines in response to PEITC treatment. Substantial cleavage of caspase 3 and poly-ADP ribose polymerase (PARP) were associated with PEITC-mediated apoptosis in MDA-MB-231 and MCF-7 cells. Notably, transient silencing of HER2 decreased and overexpressing HER2 increased the effects of PEITC. Furthermore, reactive oxygen species (ROS) generation, mitochondrial depolarization and apoptosis by PEITC treatment were much higher in breast cancer cells expressing higher levels of HER2 (HH) as compared to parent cell lines. The IC50 of PEITC following 24 h of treatment was reduced remarkably to 5 μM in MDA-MB-231 (HH) and 4 μM in MCF-7 (HH) cells, stably overexpressing HER2. Oral administration of 12 μM PEITC significantly suppressed the growth of breast tumor xenografts in SCID/NOD mice. In agreement with our in vitro results, tumors from PEITC-treated mice demonstrated reduced HER2, EGFR and STAT3 expression and increased apoptosis as revealed by cleavage of caspase 3 and PARP. In addition our results show that PEITC can enhance the efficacy of doxorubicin.
Our results show a unique specificity of PEITC in inducing apoptosis in HER2-expressing tumor cells in vitro and in vivo and enhancing the effects of doxorubicin. This unique specificity of PEITC offers promise to a subset of breast cancer patients overexpressing HER2.
Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anticancer agents to cross the blood-brain-barrier represents a critical challenge for ...successful treatment. In the current study, we investigated the antimetastatic potential of penfluridol, an antipsychotic drug frequently prescribed for schizophrenia with anticancer activity. We show that penfluridol induced apoptosis and reduced the survival of several metastatic triple-negative breast cancer (TNBC) cell lines. In addition, penfluridol treatment significantly reduced the expression of integrin α6, integrin β4, Fak, paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of penfluridol in three different in vivo tumor models. We demonstrate that penfluridol administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, penfluridol treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. Penfluridol-treated tumors from all three models exhibited reduced integrin β4 and increased apoptosis. Moreover, chronic administration of penfluridol failed to elicit significant toxic or behavioral side effects in mice. Taken together, our results indicate that penfluridol effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing penfluridol for the treatment of metastatic TNBC.
We evaluated the mechanism of capsaicin-mediated ROS generation in pancreatic cancer cells. The generation of ROS was about 4-6 fold more as compared to control and as early as 1 h after capsaicin ...treatment in BxPC-3 and AsPC-1 cells but not in normal HPDE-6 cells. The generation of ROS was inhibited by catalase and EUK-134. To delineate the mechanism of ROS generation, enzymatic activities of mitochondrial complex-I and complex-III were determined in the pure mitochondria. Our results shows that capsaicin inhibits about 2.5-9% and 5-20% of complex-I activity and 8-75% of complex-III activity in BxPC-3 and AsPC-1 cells respectively, which was attenuable by SOD, catalase and EUK-134. On the other hand, capsaicin treatment failed to inhibit complex-I or complex-III activities in normal HPDE-6 cells. The ATP levels were drastically suppressed by capsaicin treatment in both BxPC-3 and AsPC-1 cells and attenuated by catalase or EUK-134. Oxidation of mitochondria-specific cardiolipin was substantially higher in capsaicin treated cells. BxPC-3 derived ρ(0) cells, which lack mitochondrial DNA, were completely resistant to capsaicin mediated ROS generation and apoptosis. Our results reveal that the release of cytochrome c and cleavage of both caspase-9 and caspase-3 due to disruption of mitochondrial membrane potential were significantly blocked by catalase and EUK-134 in BxPC-3 cells. Our results further demonstrate that capsaicin treatment not only inhibit the enzymatic activity and expression of SOD, catalase and glutathione peroxidase but also reduce glutathione level. Over-expression of catalase by transient transfection protected the cells from capsaicin-mediated ROS generation and apoptosis. Furthermore, tumors from mice orally fed with 2.5 mg/kg capsaicin show decreased SOD activity and an increase in GSSG/GSH levels as compared to controls. Taken together, our results suggest the involvement of mitochondrial complex-I and III in capsaicin-mediated ROS generation and decrease in antioxidant levels resulting in severe mitochondrial damage leading to apoptosis in pancreatic cancer cells.
Immune check point inhibitors (ICIs) have marked their existence in the field of cancer immunotherapy. Their existence dates to 2011 when the first anti-cytotoxic T lymphocyte-associated protein 4 ...(CTLA-4) got its FDA approval for the management of metastatic melanoma. The class of ICIs now also include antibodies against programmed cell death-1 (PD-1) and its ligand (PD-L1) which immediately gained FDA approval for use against multiple cancer types because of their effect on patient survival. These discoveries were followed by a significant rise in the identification of novel ICIs with potential anti-tumor response. Researchers have identified various novel checkpoint inhibitors which are currently under clinical trials. Despite the success of ICIs, only a small subset of patients with specific tumor types achieves a promising response. Not only efficient therapeutic response but also development of resistance, recurrence and other immune-related adverse effects limit the applicability of immune checkpoint inhibitors. These challenges can only be addressed when a directed approach is implemented at both basic and translational level. In this review, we have briefly discussed the history of ICIs, the next generation of inhibitors which are currently under clinical trial and mechanisms of resistance that can lead to treatment failure. Ultimately, by combining these insights researchers might be able to achieve a more durable and effective response in cancer patients.
Paclitaxel is a first line chemotherapeutic agent for the patients with metastatic breast cancer. But inherited or acquired resistance to paclitaxel leads to poor response rates in a majority of ...these patients. To identify mechanisms of paclitaxel resistance, we developed paclitaxel resistant breast cancer cell lines, MCF-7 and 4T1 by continuous exposure to paclitaxel for several months. Western blot analysis showed increased expression of HER2 and β-catenin pathway in resistant cell lines as compared to parent cells. Hence, we hypothesized that HER2/β-catenin mediates paclitaxel resistance in breast cancer and suppression of HER2/β-catenin signaling could overcome paclitaxel resistance. Our data showed that penfluridol (PFL) treatment significantly reduced the survival of paclitaxel-resistant cells. Western blot analysis revealed that PFL treatment suppressed HER2, as well as, β-catenin pathway. In vivo data confirmed that PFL significantly potentiated tumor growth suppressive effects of paclitaxel in an orthotropic breast cancer model. In addition, tumors from paclitaxel and PFL-treated mice showed reduced HER2 and β-catenin expression, along with increased apoptosis. Taken together our results demonstrate a novel role of HER2/β-catenin in paclitaxel resistance and open up new avenues for application of PFL as a therapeutic option for overcoming paclitaxel resistance.
Cancer cells stemness: A doorstep to targeted therapy Prasad, Sahdeo; Ramachandran, Sharavan; Gupta, Nehal ...
Biochimica et biophysica acta. Molecular basis of disease,
04/2020, Letnik:
1866, Številka:
4
Journal Article
Recenzirano
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Recent advances in research on cancer have led to understand the pathogenesis of cancer and development of new anticancer drugs. Despite of these advancements, many tumors have been found to recur, ...undergo metastasis and develop resistance to therapy. Accumulated evidences suggest that small population of cancer cells known as cancer stem cells (CSC) are responsible for reconstitution and propagation of the disease. CSCs possess the ability to self-renew, differentiate and proliferate like normal stem cells. CSCs also appear to have resistance to anti-cancer therapies and subsequent relapse. The underlying stemness properties of the CSCs are reliant on multiple molecular targets such as signaling pathways, cell surface molecules, tumor microenvironment, apoptotic pathways, microRNA, stem cell differentiation, and drug resistance markers. Thus an effective therapeutic strategy relies on targeting CSCs to overcome the possible tumor relapse and chemoresistance. The targeted inhibition of these stem cell biomarkers is one of the promising approaches to eliminate cancer stemness. This review article summarizes possible targets of cancer cell stemness for the complete treatment of cancer.
•Cancer stem cells play crucial role in recurrence, metastasis and resistance to treatment.•Cancer stem cells express defining molecular targets.•Cancer can be eliminated by modulating cancer stem cell markers.
Breast cancer is the second leading cause of cancer-related mortality in women. In the current study, we evaluated the anticancer effects of an antiprotozoal drug, atovaquone, against several breast ...cancer cell lines. Our results showed that atovaquone treatment induced apoptosis and inhibited the growth of all the breast cancer cell lines tested, including several patient-derived cells. In addition, atovaquone treatment significantly reduced the expression of HER2, β-catenin, and its downstream molecules such as pGSK-3β, TCF-4, cyclin D1, and c-Myc
Efficacy of atovaquone was further evaluated in an
tumor model by orthotropic implantation of two highly aggressive 4T1 and CI66 breast cancer cells in the mammary fat pad of female mice. Our results demonstrated that oral administration of atovaquone suppressed the growth of CI66 and 4T1 tumors by 70% and 60%, respectively. Paclitaxel is the first-line chemotherapeutic agent for metastatic breast cancer. We demonstrate that atovaquone administration suppressed the growth of 4T1 paclitaxel-resistant tumors by 40%. Tumors from atovaquone-treated mice exhibited reduced HER2, β-catenin, and c-Myc levels alongside an increase in apoptosis in all the three tumor models when analyzed by Western blotting, IHC, and TUNEL assay. Taken together, our results indicate that atovaquone effectively reduces the growth of primary and paclitaxel-resistant breast tumors. Atovaquone is already in the clinics with high safety and tolerability profile. Therefore, the findings from our studies will potentially prompt further clinical investigation into repurposing atovaquone for the treatment of patients with advanced breast cancer.
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