Kapil Mehta | University of Texas M. D. Anderson Cancer Center (original) (raw)

Papers by Kapil Mehta

Infection and Immunity, Feb 1, 1985

The Journal of Immunology

Mouse resident peritoneal macrophages, activated in vitro with murine recombinant interferon-gamm... more Mouse resident peritoneal macrophages, activated in vitro with murine recombinant interferon-gamma and lipopolysaccharide in the presence of sera from different sources, showed marked differences in their abilities to inhibit murine adenocarcinoma cell growth, and in induced activity of the enzyme, tissue transglutaminase. The extraction of lipids from the serum abolished its ability to induce tissue TGase activity and to inhibit cytostatic activity, but these capabilities were fully restored by readdition of all trans-retinol or all trans-retinoic acid at physiological concentrations. Addition of dansylcadaverine, a competitive inhibitor of TGase, resulted in complete recovery of macrophages from retinoid-induced suppression of cytostatic activity. These results suggest that endogenous retinoids play an important role in the regulation of macrophage-mediated cytostatic activity in a process that is independent of prostaglandin secretion but seems to involve the protein cross-linkin...

Journal of Clinical Microbiology, 1978

Sera from cases of elephantiasis due to Wuchereria bancrofti infection promoted an intense adhesi... more Sera from cases of elephantiasis due to Wuchereria bancrofti infection promoted an intense adhesion of peripheral blood leukocytes to W. bancrofti microfilariae in vitro. A similar adhesion was also seen using sera from some normal persons living for several years in areas where filariasis is endemic. No such adhesion was evident with sera from microfilaria carriers or from normal subjects from nonendemic areas. The adhesion was complement independent and was associated with the immunoglobulin G fraction of serum. 51Cr release studies suggested the occurrence of cell-mediated cytotoxicity to W. bancrofti microfilariae in the presence of elephantiasis serum. Microfilariae of Litomosoides carinii could be isolated free of blood cells, from the blood of infected rats. In the presence of serum, or its immunoglobulin G fraction, from patients with elephantiasis, L. carinii microfilariae adhered to human peripheral blood leukocytes or rat spleen cells.

Frontiers in Oncology, 2020

Cancer stem cells (CSCs) are a small and elusive subpopulation of self-renewing cancer cells with... more Cancer stem cells (CSCs) are a small and elusive subpopulation of self-renewing cancer cells with remarkable ability to initiate, propagate, and spread the malignant disease. In addition, they exhibit increased resistance to anticancer therapies, thereby contributing to disease relapse. CSCs are reported to be present in many tumor types such as melanoma, sarcoma, mammary tumors, colon cancer and other solid tumors. These cells from different tumors show unique energetic and metabolic pathways. For example, CSCs from one type of tumor may predominantly use aerobic glycolysis, while from another tumor type may utilize oxidative phosphorylation. Most commonly these cells use fatty acid oxidation and ketone bodies as the main source of energy production. CSCs have a remarkable ability to reprogram their metabolism in order to survive under adverse conditions such as hypoxia, acidosis, and starvation. There is increasing interest to identify molecular targets that can be utilized to kill CSCs and to control their growth. In this review, we discuss how an understanding of the unique metabolism of CSCs from different tumors can offer promising strategies for targeting CSCs and hence to prevent disease relapse and to treat the metastatic disease.

Journal of Leukocyte Biology, 1990

The effect of retinoic acid (RA) and retinol (ROH) on the release of tumor necrosis factor (TNF) ... more The effect of retinoic acid (RA) and retinol (ROH) on the release of tumor necrosis factor (TNF) by human peripheral blood monocytes (HPBM) was determined. HPBM were cultured for various periods of time in either 5% complete (cAB) or delipidized (DLS) AB serum. TNF release (L929 cytolytic assay) in the presence of cAB occurred during the first 3 days of in vitro culture. Delipidization of AB serum completely inhibited the lipopolysaccharide (LPS)-induced release of TNF by HPBM. Addition of RA (0.5 μM) to DLS restored LPS-induced TNF release by HPBM, and supplementation with ROH (1.0 μM) resulted in release of TNF-like activity, but only after 3 days of in vitro culture. The maintenance of TNF release by the addition of exogenous RA after 3 days of in vitro culture suggested that depletion of endogenous RA was partially responsible for loss of TNF-like activity. The levels of endogenous TNF protein and mRNA were not influenced by delipidization of serum and were found to be similar t...

Parasite, 1999

Transglutaminases (E.C. 2.3.3.13) are a family of Ca 2+-dependent enzymes that stabilize protein ... more Transglutaminases (E.C. 2.3.3.13) are a family of Ca 2+-dependent enzymes that stabilize protein structure by catalyzing the formation of isopeptide bonds. A novel form of transglutaminase has been identified and characterized that seem to play an important role in growth, development, and molting in adult and larval stages of filarial nematodes. The aim of this study was to identify the ubiquitous nature of this enzyme in other nematodes and to measure its significance to larval growth, molting, and development. For this purpose, equine Strongylus spp. were used. Activity of this enzyme was identified in extracts of larvae and adults of Strongylus vulgaris, S. edentatus, Parascaris equorum and Cylicocyclus insigne. The significance of transglutaminase in the early growth and development of Strongylus vulgaris, S. edentatus and S. equinus was tested by adding specific inhibitors, monodansylcadaverine (MDC) or cystamine (CS), to in vitro cultures of third (L3) and fourth stage larvae (L4). The viability, molting and growth of these nematode species were affected by both inhibitors. Cystamine promoted abnormal development of Strongylus edentatus L3, resulting in an aberrant expansion of the anterior end. Addition of these inhibitors to cultures of L4 also reduced growth of the three species. The results indicated that transglutaminase is present in a wide array of nematode parasites and may be important in growth and development of their larval stages.

Anticancer research, 2010

The third International Translational Cancer Research symposium on "Cell Signaling and Cance... more The third International Translational Cancer Research symposium on "Cell Signaling and Cancer" was recently (from Dec. 18th through Dec. 21st, 2009) convened in Bhubaneswar, Orissa, which lies along the eastern shores of India, just south of Bengal. Overall, the meeting provided a platform for scientists from different nations to discuss emerging ideas that focused on cell signaling in cancer. This third in a row symposium tried to bridge the gap not only between basic research and clinical trials, but also between developed nations and developing countries. With the continuing success of these meetings, the fourth International Translational Cancer Research Meeting is slated to be in December 2011. Please contact us if you are interested in participating, presenting, or supporting the next conference.

Indian journal of experimental biology, 2004

Prokaryotes and various eukaryotes have remarkable ability to survive under adverse physiologic c... more Prokaryotes and various eukaryotes have remarkable ability to survive under adverse physiologic conditions and protect themselves from environmental stresses. An important mechanism by which they accomplish this is by synthesizing rigid and biochemically inert structures around them. In general, these structures are highly stable and resistant to mechanical and chemical insults. Biochemically, they are composed of complex carbohydrates, such as chitin and heavily crosslinked scaffold of proteins to form complex structures, such as sheath, cuticle, and epicuticle. Transglutaminases (TGases) are a family of enzymes that share catalytic function with thioredoxin and protein disulphide isomerases (PDI) and catalyze protein crosslink reaction by establishing epsilon-(gamma-glutamyl)lysine isopeptide bonds. The isopeptide bonds thus formed are of great physiologic significance because once formed, they cannot be hydorlysed by any known enzymes of the eukaryote system and exhibit high resi...

Indian Journal of Clinical Biochemistry, 1997

A rational approach for developing effective filaricides awaits greater knowledge on the biochemi... more A rational approach for developing effective filaricides awaits greater knowledge on the biochemical pathways operating in filarial parasites. For example, metabolic pathways or key enzymes that are so pivotal to the parasite that their interruption or inhibition causes spontaneous death, could be exploited to develop effective chemotherapeutic agents. Similarly, developing a safe and nontoxic filaricidal will require precise understanding of whether or not the potential molecular target in the parasite is unique or at least different enough from the host system. Recently, we identified a novel transglutaminase enzyme (EC2.3.2.13; TGase) in filarial parasites that plays an important role during their normal growth and development. Based on these principles, TGase may serve as a new target for the development of effective chemotherapeutic agent and vaccine for controlling and preventing the infections caused by these parasites.

PLoS ONE, 2013

We present a novel study on label-free recognition and distinction of drug resistant breast cance... more We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX) from their parental cells (MCF-7 WT) via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (R extra). Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher R extra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.

Molecular Cancer Therapeutics, 2007

The role of curcumin (diferuloylmethane), a proapoptotic compound, for the treatment of cancer ha... more The role of curcumin (diferuloylmethane), a proapoptotic compound, for the treatment of cancer has been an area of growing interest. Curcumin in its free form is poorly absorbed in the gastrointestinal tract and therefore may be limited in its clinical efficacy. Liposome encapsulation of this compound would allow systemic administration. The current study evaluated the preclinical antitumor activity of liposomal curcumin in colorectal cancer. We also compared the efficacy of liposomal curcumin with oxaliplatin, a standard chemotherapy for this malignancy. In vitro treatment with liposomal curcumin induced a dose-dependent growth inhibition [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt] and apoptosis [poly(ADP-ribose) polymerase] in the two human colorectal cancer cell lines tested (LoVo and Colo205 cells). There was also synergism between liposomal curcumin and oxaliplatin at a ratio of 4:1 in LoVo cells in vitro. In vivo, significant...

CancerSpectrum Knowledge Environment, 2002

Two recent correspondences published in the Journal (1,2) labeled the MCF-7/ADR cell line-a multi... more Two recent correspondences published in the Journal (1,2) labeled the MCF-7/ADR cell line-a multidrugresistant (MDR) human breast cancer MCF-7 subline-as having a non-MCF-7 origin, which led to a change in the nomenclature of this cell line to NCI/ ADR. We believe the original nomenclature of MCF-7/ADR should be retained. Although the two MDR MCF-7 sublines (MCF-7/ADR and MCF-7 TH) used by the investigators whose work prompted the nomenclature change were independently established, they showed several genotypic and phenotypic similarities. Both contained a full-length functional caspase-3 protein (2), despite complete loss of this protein in the parental MCF-7 cells because of a 47base-pair deletion in exon 3 of the CASP-3 gene (3). Interestingly, several features of the MCF-7/DOX subline established in our laboratory several years ago (4) were identical to those of the MCF-7/ADR and MCF-7 TH cells but different from those of the parental MCF-7 cells (5). For example, similar to MCF-7/ADR and MCF-7 TH cells, the MCF-7/DOX cells showed high expression levels of P-glycoprotein (P-gp) and of a protein cross-linking enzyme, tissue transglutaminase; they also contained the full-length caspase-3 protein (6). We thus sought to determine whether the development of drug resistance in MCF-7 cells represents selective selection and expansion of an inherently resistant 1652 CORRESPONDENCE

The Journal of experimental medicine, 1984

The levels and activity of tissue transglutaminase were studied in human peripheral blood monocyt... more The levels and activity of tissue transglutaminase were studied in human peripheral blood monocytes during differentiation into macrophages in vitro. The enzyme was present at low levels in freshly isolated monocytes (less than 20 ng/mg cell protein) but increased 50-fold during 10 d of adherent culture in autologous serum, reaching levels of 0.1% of total cellular protein. The rate of appearance of tissue transglutaminase in monocytes was accelerated by low levels of lipopolysaccharide. The half-life of disappearance of transglutaminase from human monocytes was 11 and 7 h in 2-d-old and 10-d-old cells, respectively. Treatment of 1-day-old monocytes with actinomycin D for 24 h blocked the increase in transglutaminase levels. These results indicated that the induction of gene transcription and protein synthesis was responsible for the increased transglutaminase levels and activity observed with cultured human monocytes. The induction of tissue transglutaminase may be a component in t...

Biology of Reproduction, 1989

Sperm antigens were assessed for their ability to induce cell-mediated immune (CMI) responses. Pu... more Sperm antigens were assessed for their ability to induce cell-mediated immune (CMI) responses. Purified fertilization antigen (FA-I), protamine, and the lithium diiodosalicylate (LJS)-solubilized sperm preparation activated presensitized lymphocytes to secrete soluble mediators that activated macrophages and significantly inhibited sperm motility and embryonic development. The FA-), however, was the most potent antigen in inducing proliferative response as well as the release of soluble mediators. US-sperm preparation, which contained numerous antigens, showed the least activity. The unsensitized control spleen cells did not secrete any factor(s) when activated with the antigen. In conclusion, these results indicate that sperm antigens can specifically induce (CMI) factors that have detrimental effects on sperm motility and pre#{252}nplantation embryos. These findings may have potential clinical implications for humans, especially in immwwlogic and unexplained infertility, recurrent abortions, and development of antisperm contraceptive vaccines.

Antimicrobial Agents and Chemotherapy, 1995

Highly insoluble proteins, which are probably cross-linked, are common in the cuticle and epicuti... more Highly insoluble proteins, which are probably cross-linked, are common in the cuticle and epicuticle of filarial parasites and other nematode species. We have investigated the possible involvement of transglutaminase (TGase)-catalyzed reactions in the development of Onchocerca volvulus fourth-stage larvae (L4) by testing the effects of TGase inhibitors on the survival of third-stage larvae (L3) and the molting of L3 to L4 in vitro. The larvae were cultured in the presence of three specific TGase inhibitors: monodansylcadaverine, cystamine, and N-benzyloxycarbonyl-D,L-beta-(3-bromo-4,5-dihydroisoxazol-5-yl)-al anine benzylamide. None of the inhibitors reduced the viability of either L3 or L4. However, the inhibitors reduced, in a time- and dose-dependent manner, the number of L3 that molted to L4 in vitro. Molting was completely inhibited in the presence of 100 to 200 microM inhibitors. Ultrastructural examination of L3 that did not molt in the presence of monodansylcadaverine or cys...

Antimicrobial Agents and Chemotherapy, 1984

Oncogene, 2006

The development of resistance to chemotherapeutic drugs is a major obstacle to the successful tre... more The development of resistance to chemotherapeutic drugs is a major obstacle to the successful treatment of breast cancer. Ways to block or overcome this resistance are objects of intense research. We have previously shown that cancer cells selected for resistance against chemotherapeutic drugs or isolated from metastatic tumor sites have high levels of a calcium-dependent protein crosslinking enzyme, tissue transglutaminase (TG2) but no direct link between TG2 and resistance was established. As TG2 can associate with the b members of the integrin family of proteins, we hypothesized that TG2 promotes cell survival signaling pathways by activating integrins on the surface of these cells. To test this hypothesis, we studied the expression of TG2 and its interaction with various integrins in drug-resistant MCF-7 breast cancer cells. TG2 closely associated with b1 and b5 integrins on the surface of drug-resistant MCF-7 (MCF-7/Dox and MCF-7/RT) cells. The incubation of TG2-expressing drug-resistant MCF-7 cells on fibronectin (Fn)-coated surfaces strongly activated focal adhesion kinase, an event that leads to the activation of several downstream signaling pathways and, in turn, can confer apoptosisresistant phenotype to cancer cells. The role of TG2 in Fnmediated cell attachment, cell growth, and cell survival functions was further analysed by small interfering RNA (siRNA) approach. Inhibition of TG2 by siRNA-inhibited Fn-mediated cell attachment and cell survival functions in drug-resistant MCF-7 cells. We conclude that the expression of TG2 in breast cancer cells contributes to the development of the drug-resistance phenotype by promoting interaction between integrins and Fn.

Anticancer research, 2013

Like most countries in the Western world, most non-communicable diseases, such as cancer, are ver... more Like most countries in the Western world, most non-communicable diseases, such as cancer, are very much on the rise. Extensive research suggests that cancer is a preventable disease that requires a major change in lifestyle. The fourth International Translational Cancer Research Symposium on Cancer Prevention was convened from Dec. 16th through Dec. 19th, 2011 in Udaipur, Rajasthan, the largest state located on the northwestern side of India. Scientists, clinicians, and trainees from different countries participated in this conference to discuss biological processes involved in cancer and various avenues to prevent cancer. It became clear from this conference that tobacco use, alcohol consumption, diet and obesity, radiation, and pollution may account for many carcinomas.

Breast Cancer Research, 2013

Breast cancer is the most common malignancy diagnosed among women worldwide and is the second lea... more Breast cancer is the most common malignancy diagnosed among women worldwide and is the second leading cause of cancer-related deaths in women [1]. Early detec tion, improved surgical techniques, and targeted thera pies have resulted in a general downward trend in the prevalence of the disease. However, recurrence of cancer owing to metastasis and emergence of drug resistance still account for more than 90% of cancer-related deaths and continue to pose major clinical challenges in the successful treatment of the disease. Th e high rate of relapse in patients with breast cancer-estimated to be approximately 30%-underscores the need to identify tumorencoded genes and to understand how these genes contribute to metastasis. Such an understanding will enable novel strategies (a) to prevent the progression of early lesions to metastatic disease, (b) to treat metastatic disease, and (c) to stratify tumors with high metastatic potential. Although genetic changes are central to many aspects of cancer development, they are not suffi cient to cause disease progression. In addition to these genetic alterations, early-stage tumors (for example, ductal carcinoma in situ (DCIS) of the breast) require some ancillary changes (induced by the tumor microenviron ment) to become invasive and to metastasize [2]. Many infl am matory mediators produced in the tumor milieu can induce persistent epigenetic changes that aff ect fundamental processes necessary for generating tumor cell variants with metastatic ability [2]. However, infor mation on how and what infl ammation-induced epi genetic changes aff ect invasion and metastasis remains elusive. Recently, we identifi ed a novel infl ammatory pathway that is constitutively activated in cancer cells and promotes drug resistance and an invasive phenotype in epithelial cancer cells [3]. Central to this pathway is increased expression of the structurally and functionally complex protein called tissue transglutaminase (TG2 or tTG). In this review, we discuss the evidence that aberrant expression of TG2 promotes a metastatic and drug-resistant phenotype in breast epithelial cells by inducing the developmentally regulated program of epithelial-to-mesenchymal transition (EMT) and conferring stem cell traits to the cells.