Suresh Guruswamy's scientific contributionswhile working at University of Oklahoma Health Sciences Center (Oklahoma City, United States) and other institutions

Publications (19)

Publications citing this author (533)

    • The ratio of Bax to Bcl-2 has been shown to be a key determinant that can drive the initiation of apoptosis. SHetA2 reduces the expression of Bcl-2, but not Bax in cancer cells in vitro [7, 13, 26] and tumors in vivo[9] leading to induction of the intrinsic apoptosis pathway, while mortalin can prevent reduction of Bcl-2 and conformational changes in Bax leading to inhibition of the intrinsic apoptosis pathway444546.
    [Show abstract] [Hide abstract] ABSTRACT: SHetA2 is a small molecule flexible heteroarotinoid (Flex-Het) with promising cancer prevention and therapeutic activity. Extensive preclinical testing documented lack of SHetA2 toxicity at doses 25 to 150 fold above effective doses. Knowledge of the SHetA2 molecular target(s) that mediate(s) the mechanism of SHetA2 action is critical to appropriate design of clinical trials and improved analogs. The aim of this study was to develop a method to identify SHetA2 binding proteins in cancer cells. A known metabolite of SHetA2 that has a hydroxyl group available for attachment was synthesized and conjugated to a linker for attachment to a magnetic microsphere. SHetA2-conjugated magnetic microspheres and unconjugated magnetic microspheres were separately incubated with aliquots of a whole cell protein extract from the A2780 human ovarian cancer cell line. After washing away non-specifically bound proteins with the protein extraction buffer, SHetA2-binding proteins were eluted with an excess of free SHetA2. In two independent experiments, an SDS gel band of about 72 kDa was present at differential levels in wells of eluent from SHetA2-microspheres in comparison to wells of eluent from unconjugated microspheres. Mass spectrometry analysis of the bands (QStar) and straight eluents (Orbitrap) identified mortalin (HSPA9) to be present in the eluent from SHetA2-microspheres and not in eluent from unconjugated microspheres. Co-immunoprecipitation experiments demonstrated that SHetA2 interfered with mortalin binding to p53 and p66 Src homologous-collagen homologue (p66shc) inside cancer cells. Mortalin and SHetA2 conflictingly regulate the same molecules involved in mitochondria-mediated intrinsic apoptosis. The results validate the power of this protocol for revealing drug targets. Electronic supplementary material The online version of this article (doi:10.1007/s10637-013-0041-x) contains supplementary material, which is available to authorized users.
    Full-text · Article · Nov 2013
    • [32] Cervical cancer Growth inhibition by micromolar concentrations. [5] Kidney
    Full-text · Chapter · Dec 2016 · Nutrition
    • Elevated production of endogenous PGI 2 enhanced PPARa translocation from the cytosol to the nucleus which could protect renal tubular cells from I/R induced apoptosis (Chen et al., 2009). Therefore, it is suggested that protective effects of APN on the kidney post I/R injury may include: (1) PGE 2 possess anti-apoptotic or anti-inflammatory effects on renal tubular cells (Elberg et al., 2007); (2) PGI 2 not only inhibits renal apoptosis but may influence PPARa translocation to attenuate cytokine production via NFkB pathway (Chen et al., 2009); and (3) up-regulation of the protective gene, HO-1, by APNinduced PPARa pathway may contribute significantly to their anti-inflammatory or anti-apoptosis properties. In addition, (4) AMPK kinase pathway has demonstrated its protective effect against inflammation induced chronic renal injury and lastly (Ouchi et al., 2004; Li et al., 2010), (5) APNR1 and APNR2 adaptor protein (APPL1) protein has implicated its regulation on APN transduction to activate ERK1/2 MAP kinase and Ca 2þ / calmodulin-dependent protein kinase kinase (CaMKK) pathway (Mao et al., 2006; Zhou et al., 2009).
    File · Data · Oct 2012 · Nutrition
    • It is noteworthy that HPV, a major risk factor for vulvar cancer [4, 66], requires p63 for its late viral functions [67]. While SW962 cells are HPV negative [68], almost 40% of our FFPE samples were demonstrated to be HPV positive. However, no association between p63 expression and HPV status was achieved.
    [Show abstract] [Hide abstract] ABSTRACT: MiR-223-5p has been previously mentioned to be associated with tumor metastasis in HPV negative vulvar carcinomas, such as in several other tumor types. In the present study, we hypothesized that this microRNA would be important in vulvar cancer carcinogenesis and progression. To investigate this, we artificially mimicked miR-223-5p expression in a cell line derived from lymph node metastasis of vulvar carcinoma (SW962) and performed in vitro assays. As results, lower cell proliferation (p < 0.01) and migration (p < 0.001) were observed when miR-223-5p was overexpressed. In contrast, increased invasive potential of these cells was verified (p < 0.004). In silico search indicated that miR-223-5p targets TP63, member of the TP53 family of proteins, largely described with importance in vulvar cancer. We experimentally demonstrated that this microRNA is capable to decrease levels of p63 at both mRNA and protein levels (p < 0.001, and p < 0.0001; respectively). Also, a significant inverse correlation was observed between miR-223-5p and p63 expressions in tumors from patients (p = 0.0365). Furthermore, low p63 protein expression was correlated with deeper tumor invasion (p = 0.0491) and lower patient overall survival (p = 0.0494). Our study points out miR-223-5p overexpression as a putative pathological mechanism of tumor invasion and a promising therapeutic target and highlights the importance of both miR-223-5p and p63 as prognostic factors in vulvar cancer. Also, it is plausible that the evaluation of p63 expression in vulvar cancer at the biopsy level may bring important contribution on prognostic establishment and in elaborating better surgical approaches for vulvar cancer patients.
    Full-text · Article · Jun 2016
    • In contrast, WT1 is expressed not only in renal precursors, but also in mature podocytes in the adult kidney (Kann et al., 2015;Kreidberg, 2010). Other markers like paired box (PAX)2, which are widely expressed in vivo during many stages of renal development, but not in mature renal cells, become re-expressed in mature renal cells under in vitro conditions (Elberg et al., 2008). Therefore, the state of PSC-derived cells cannot be reliably identified by their marker expression patterns only, and it is important to test also other properties of the obtained structures and cell types.
    [Show abstract] [Hide abstract] ABSTRACT: The global rise in the numbers of kidney patients and the shortage in transplantable organs have led to an increasing interest in kidney-specific regenerative therapies, renal disease modelling and bioartificial kidneys. Sources for large quantities of high-quality renal cells and tissues would be required, also for applications in in vitro platforms for compound safety and efficacy screening. Stem cell-based approaches for the generation of renal-like cells and tissues would be most attractive, but such methods were not available until recently. This situation has drastically changed since 2013, and various protocols for the generation of renal-like cells and precursors from pluripotent stem cells (PSC) have been established. The most recent breakthroughs were related to the establishment of various protocols for the generation of PSC-derived kidney organoids. In combination with recent advances in genome editing, bioprinting and the establishment of predictive renal screening platforms this results in exciting new possibilities. This review will give a comprehensive overview over current PSC-based protocols for the generation of renal-like cells, precursors and organoids, and their current and potential applications in regenerative medicine, compound screening, disease modelling and bioartificial organs.
    Full-text · Article · Dec 2016
    • All of the above mentioned findings let us to think that CAV-1 has an important role to generate new capillary networks in tumor- igenesis [26].Table 2 [28] demonstrated in cell culture setup that CAV-1 inhibition caused a distinct decline in the cell viability in terms of mRNA expressions. Other similar studies have pointed out the possibilities for CAV-1 inhibition to lead the development of new chemotherapeutic agents by using these findings [26,29,30]. Nimri et al. determined that CAV-1 expression was absent in high metastatic cell series, whereas CAV-1 expression was shown in weak metastatic cell series in cytosolic cell fractions [21].
    Full-text · Article · Jan 2016 · Nutrition
    • Similar results regarding pAMPK were found in epitrochlearis muscle (not shown). AMPK regulates GLUT4 abundance by increasing the activity of the transcription factor Mef2A (Thai et al., 1998). Both GLUT4 total content and Mef2A nuclear content was similar in soleus muscle from BHE/cdb and CD rats (Fig. 4B, C).
    [Show abstract] [Hide abstract] ABSTRACT: The BHE/cdb rat has a mutation in adenosine triphosphate (ATP) synthase that impairs insulin secretion. However, male BHE/cdb rats have normal circulating glucose and enhanced glucose tolerance. The aim of the current study was to identify mechanisms of enhanced glucose tolerance. The respiratory exchange ratio was increased, indicating increased oxidation of carbohydrate in BHE/cdb rats, consistent with increases in liver pyruvate dehydrogenase activity and muscle citrate synthase activity. Liver also exhibited diminished phosphoenol pyruvate carboxykinase content, which correlated with a decreased counter-regulatory response in the insulin tolerance test. Signaling via Akt or AMP-dependent kinase pathways in the liver could not account for lower blood glucose. We conclude that chronically low insulin secretion leads to adaption in glucose metabolism primarily in liver to maintain euglycemia.
    Full-text · Article · Apr 2013
    • However, in vivo-based experiments with p53 SMWC agents showed that they had only a noticeable but not significant impact on tumor-free survival in the MCA mouse tumor model. This lack of efficacy in the MCA model is in marked contrast to the well-documented efficacy of these p53 SMWC in several other primary murine tumor model systems [28][29][30][31]. Importantly, their modest effect in vivo on MCA mice was not due to the outgrowth of p53 SMWC resistant tumor cells, since our in vitro-based analysis indicated that early passage cell lines derived from tumors induced in these mice were highly sensitive to p53 SMWC.
    [Show abstract] [Hide abstract] ABSTRACT: Cancer stem cells (CSC) typically over-express aldehyde dehydrogenase (ALDH). Thus, ALDHbright tumor cells represent targets for developing novel cancer prevention/ treatment interventions. Loss of p53 function is a common genetic event during cancer development wherein small molecular weight compounds (SMWC) that restore p53 function and reverse tumor growth have been identified. Here, we focused on two widely studied p53 SMWC, CP-31398 and PRIMA-1, to target ALDHbright CSC in human breast, endometrial and pancreas carcinoma cell lines expressing mutant or wild type (WT) p53. CP-31398 and PRIMA-1 significantly reduced CSC content and sphere formation by these cell lines in vitro. In addition, these agents were more effective in vitro against CSC compared to cisplatin and gemcitabine, two often-used chemotherapeutic agents. We also tested a combinatorial treatment in methylcholantrene (MCA)-treated mice consisting of p53 SMWC and p53-based vaccines. Yet using survival end-point analysis, no increased efficacy in the presence of either p53 SMWC alone or with vaccine compared to vaccine alone was observed. These results may be due, in part, to the presence of immune cells, such as activated lymphocytes expressing WT p53 at levels comparable to some tumor cells, wherein further increase of p53 expression by p53 SMWC may alter survival of these immune cells and negatively impact an effective immune response. Continuous exposure of mice to MCA may have also interfered with the action of these p53 SMWC, including potential direct interaction with MCA. Nonetheless, the effect of p53 SMWC on CSC and cancer treatment remains of great interest.
    Full-text · Article · Apr 2016
    • As reported before, statins can be used as co-adjuvants of classic chemotherapeutic drugs, as well as of more recent small molecules targeting tyrosine kinase receptors, often linked to resistance mechanisms induction. In this context, in vitro collected evidence reported the synergistic anticancer effects of statins with chemotherapeutic drugs able to induce apoptosis, such as 5-fluoruracil and cisplatin [63] , with cetuximab showing antiproliferative effects in K-Ras mutant cells [64], with doxorubicin via NFkB pathway [65,66], or with the anti-inflammatory celecoxib responsible for the inhibition of invasiveness properties by the suppression of caveolin-1 [67]. The anti-proliferative effects of statins in head and neck squamous cell carcinoma (HNSCC) cell lines and in primary cells derived from patients, tested alone or in combination with the chemotherapeutic drugs cisplatin and docetaxel, appeared to be more potent in co-administration than alone [68] .
    [Show abstract] [Hide abstract] ABSTRACT: Statins are well known competitive inhibitors of hydroxymethylglutaryl-CoA reductase enzyme (HMG-CoA reductase), thus traditionally used as cholesterol-lowering agents. In recent years, more and more effects of statins have been revealed. Nowadays alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Consequently, much attention has been directed towards the potential of statins as therapeutic agents in the oncological field. Accumulated in vitro and in vivo clinical evidence point out the role of statins in a variety of human malignancies, in regulating tumor cell growth and anti-tumor immune response. Herein, we summarize and discuss, in light of the most recent observations, the anti-tumor effects of statins, underpinning the detailed mode of action and looking for their true significance in cancer prevention and treatment, to determine if and in which case statin repositioning could be really justified for neoplastic diseases.
    Full-text · Article · Jul 2014
    • ACF have been widely used to study the potential anti-cancer properties of dietary factors or nutritional supplements against colon carcinogenesis in rodent models and may be important to help understand the earliest events of colon carcinogenesis [57, 69]. For example, bioactive compounds, such as naringin and limonin found in grapefruits, have been shown to reduce the number of ACF, in particular HMACF in azoxymethane (AOM)-treated rodent model [70].
    [Show abstract] [Hide abstract] ABSTRACT: Globally colon cancer strikes more than one million people annually and is responsible for more than half a million cancer deaths. Recent evidence suggests that the majority of malignancies, including colon cancer are driven by cancer stem cells (CSCs) that are resistant to current chemotherapeutic approaches leading to cancer relapse. Wnt signaling plays a critical role in colon stem cell (SC) renewal and carcinogenesis. Leucine-rich repeat-containing G-protein-coupled receptor 5(LGR5), a Wnt target gene, and aldehyde dehydrogenase 1B1 (ALDH1B1) are good markers for normal and malignant human colon stem cells. Diet contributes to 20-42% of all human cancers and 50-90% of colon cancer. Recent evidence shows that Western diet has a causative link to colon cancer; however, mechanisms of action are not fully elucidated. Western diet-induced obesity elevates systemic insulin-like growth factor-1 (IGF-1) and insulin levels, which could lead to elevated proliferation and suppressed apoptosis of CSCs through PI3K/AKT/Wnt pathway. Although conventional chemotherapy targets the PI3K/AKT pathways and can significantly reduce tumor size, it fails to eliminate CSCs and has serious side effects. Dietary bioactive compounds such as grape seed extract, curcumin, lycopene, and resveratrol have promising chemopreventive effects, without serious side effects on various types of cancers due to their direct and indirect actions on CSC self-renewal pathways such as the Wnt pathway. Understanding the role of CSCs in diet-induced colon cancer will aid in development of evidence-based dietary chemopreventive strategies and/or therapeutic agents targeting CSCs.
    Full-text · Article · Nov 2014
    • Some reports have indicated that Glut-4 levels are low in diabetes mellitus [48][49][50][51][52] hence, upregulation of Glut-4 transcription is seen as a means to alleviate type 2 diabetes [53][54][55][56]. Glut-4 gene is regulated by myocyte enhancing (Mef2) transcription factor which binds to its cis-elements as a hetero-dimer (Mef2a/D) resulting in Glut-4 expression [55,56]. Recent studies showed that Glut-4 expression is also regulated by nuclear respiratory factor (Nrf-1), a mitochondrial transcription factor, which controls Mef2a gene to regulate Glut-4 [57,58].
    [Show abstract] [Hide abstract] ABSTRACT: Diabetes mellitus is a metabolic disease that threatens and reduces the quality of life. Eight hybrids (1a-h) of thiosemicarbozone and triazole were screened for their effects on genes related to type 2 diabetes as well as their antioxidant activity. The influence of the hybrids on glucose transport genes (Glut-4, Mef2a and Nrf-1) was carried out using quantitative real time polymerase chain reaction (PCR). Antioxidant assays were carried out using established techniques. Hybrids 1b, 1d, 1e and 1g exhibited high expression of Glut-4 gene relative to insulin and control. All the hybrids tested except 1h and 1f expressed the Nrf-1 while only 1h did not express Mef-2a relative to control. Among all the compounds, 1b showed the highest 1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging ability and Trolox Equivalent Antioxidant Capacity (TEAC) values. In terms of Ferric Reducing Antioxidant Power (FRAP) and Oxygen Radical Absorbance Capacity (ORAC), 1c and 1d had the highest values, respectively. In all the antioxidant assays carried out, 1a was shown to have the lowest antioxidant activities. Hybrids 1d and 1g showed consistent pattern of glucose transport pathway gene transcription with all the hybrids showing antioxidant potentials though at varying extents. These hybrids could be potential candidates eliciting antidiabetic and antioxidant effects.
    Full-text · Article · Jan 2017 · Nutrition
    • She had surgery and whole brain radiation and was still alive and well 7 years post treatment for her brain metastasis. McMeekin also described a 7-year survivor [60].
    [Show abstract] [Hide abstract] ABSTRACT: Background: The management of patients with recurrent gynecological malignancy is complex, and often contentious. While historically, patients with metastases in the lungs, liver or brain have been treated with palliative intent, surgery is proving to have an increasing role in the management of such patients. Methods: In this review article, the surgical management of lung, liver and brain metastases from gynecological cancers is examined. A search of the English language literature over the last 25 years was conducted using the Medline and PubMed databases. Results: The results for management of metastases from the endometrium, ovary and cervix to the lung, brain and liver show that surprisingly good long-term survival results can be achieved for resection of metastases from all three organs. Patient selection is critical, and surgery is often used in conjunction with other treatment modalities. Conclusions: From this review, it is apparent that surgery should play an increasing role in the management of patients with parenchymal metastases from gynecological cancers. The surgery should ideally be performed in high volume, tertiary centers where there is a committed multi-disciplinary team with the necessary infrastructure to achieve the best possible outcomes in terms of both survival and morbidity.
    Full-text · Article · Dec 2016