Deep Kwatra

TARGETED LIPID BASED DRUG CONJUGATES: A NOVEL STRATEGY FOR DRUG DELIVERY

A majority of studies involving prodrugs are directed to overcome low bioavailability of the parent drug. The aim of this study is to increase the bioavailability of acyclovir (ACV) by designing a novel prodrug delivery system which is more lipophilic, and at the same time site specific. In this study, a lipid raft has been conjugated to the parent drug molecule to impart lipophilicity. Simultaneously a targeting moiety that can be recognized by a specific transporter/receptor in the cell membrane has also been tethered to the other terminal of lipid raft. Targeted lipid prodrugs i.e., biotin-ricinoleicacid-acyclovir (B-R-ACV) and biotin-12hydroxystearicacid-acyclovir (B-12HS-ACV) were synthesized with ricinoleicacid and 12hydroxystearicacid as the lipophilic rafts and biotin as the targeting moiety. Biotin-ACV (B-ACV), ricinoleicacid-ACV (R-ACV) and 12hydroxystearicacid-ACV (12HS-ACV) were also synthesized to delineate the individual effects of the targeting and the lipid moieties. Cellular accumulation studies were performed in confluent MDCK-MDR1 and Caco-2 cells. The targeted lipid prodrugs B-R-ACV and B-12HS-ACV exhibited much higher cellular accumulation than B-ACV, R-ACV and 12HS-ACV in both cell lines. This result indicates that both the targeting and the lipid moiety act synergistically toward cellular uptake. The biotin conjugated prodrugs caused a decrease in the uptake of [(3)H] biotin suggesting the role of sodium dependent multivitamin transporter (SMVT) in uptake. The affinity of these targeted lipid prodrugs toward SMVT was studied in MDCK-MDR1 cells. Both the targeted lipid prodrugs B-R-ACV (20.25 ± 1.74 μM) and B-12HS-ACV (23.99 ± 3.20 μM) demonstrated higher affinity towards SMVT than B-ACV (30.90 ± 4.19 μM). Further, dose dependent studies revealed a concentration dependent inhibitory effect on [(3)H] biotin uptake in the presence of biotinylated prodrugs. Transepithelial transport studies showed lowering of [(3)H] biotin permeability in the presence of biotin and biotinylated prodrugs, further indicating a carrier mediated translocation by SMVT. Overall, results from these studies clearly suggest that these biotinylated lipid prodrugs of ACV possess enhanced affinity towards SMVT. These prodrugs appear to be potential candidates for the treatment of oral and ocular herpes virus infections, because of higher expression of SMVT on intestinal and corneal epithelial cells. In conclusion we hypothesize that our novel prodrug design strategy may help in higher absorption of hydrophilic parent drug. Moreover, this novel prodrug design can result in higher cell permeability of hydrophilic therapeutics such as genes, siRNA, antisense RNA, DNA, oligonucleotides, peptides and proteins.

Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance.

Recently, we demonstrated that extracts of bitter melon (BME) can be used as a preventive/therapeutic agent in colon cancers. Here, we determined BME effects on anticancer activity and bioavailability of doxorubicin (DOX) in colon cancer cells. BME enhanced the effect of DOX on cell proliferation and sensitized the cells toward DOX upon pretreatment. Furthermore, there was both increased drug uptake and reduced drug efflux. We also observed a reduction in the expression of multidrug resistance conferring proteins (MDRCP) P-glycoprotein, MRP-2, and BCRP. Further BME suppressed DOX efflux in MDCK cells overexpressing the three efflux proteins individually, suggesting that BME is a potent inhibitor of MDR function. Next, we determined the effect of BME on PXR, a xenobiotic sensing nuclear receptor and a transcription factor that controls the expression of the three MDR genes. BME suppressed PXR promoter activity thereby suppressing its expression. Finally, we determined the effect of AMPK pathway on drug efflux because we have previously demonstrated that BME affects the pathway. However, inhibiting AMPK did not affect drug resistance, suggesting that BME may use different pathways for the anticancer and MDR modulating activities. Together, these results suggest that BME can enhance the bioavailability and efficacy of conventional chemotherapy.

Honokiol affects melanoma cell growth by targeting the AMP-activated protein kinase signaling pathway

BACKGROUNDnMalignant melanoma is an aggressive form of skin cancer with limited effective therapeutic options. Melanoma research concentrates on maximizing the effect on cancer cells with minimal toxicity to normal cells. AMP-activated protein kinase (AMPK) is an important regulator of cellular energy homeostasis and has been shown to control tumor progression regulating the cell cycle, protein synthesis, and cell growth and/or survival. Honokiol (HNK) is a biphenolic compound derived from Magnolia officinalis, a plant that has been used in traditional Chinese and Japanese medicine for the treatment of various pathological conditions. Recent studies have shown that HNK has antitumor activity with relatively low toxicity. In this study, we demonstrated that the growth inhibitory effects of HNK on melanoma and melanoma cancer stem cells were mediated through the activation of AMPK and hence AMPK signaling in melanoma cells.nnnMETHODSnWe determined the effects of HNK treatment on various melanoma cell lines. HNK-induced cell growth inhibitory effects were determined using hexosaminidase assay. Protein expression studies were done by immunoblotting. Primary spheroid assay was used to assess stemness by growing single suspension cells in ultralow attachment plates.nnnRESULTSnHNK is highly effective in inhibiting melanoma cells by attenuating protein kinase B/mammalian target of rapamycin and AMPK signaling. HNK showed significant inhibition of the spheroid-forming capacity of melanoma cells and, hence, stemness. HNK significantly decreased the number and size of melanospheres in a dose-dependent manner. Western blot analyses showed enhanced phosphorylation of AMPK in melanoma cells. Furthermore, HNK decreased the cellular adenosine triphosphate pool in a dose-dependent manner with maximum effects observed at 48xa0hours.nnnCONCLUSIONSnThe results suggest that HNK can target melanoma cells and mark them for cell death through AMPK signaling. Further studies are warranted for developing HNK as an effective chemopreventive/therapeutic agent in melanoma.

Molecular expression and functional activity of vitamin C specific transport system (SVCT2) in human breast cancer cells.

The main goal of this study is to investigate the expression of sodium dependent vitamin C transport system (SVCT2). Moreover, this investigation has been carried out to define uptake mechanism and intracellular regulation of ascorbic acid (AA) in human breast cancer cells (MDA-MB231, T47D and ZR-75-1). Uptake of [(14)C] AA was studied in MDA-MB231, T47D and ZR-75-1u2009cells. Functional parameters of [(14)C] AA uptake were delineated in the presence of different concentrations of unlabeled AA, pH, temperature, metabolic inhibitors, substrates and structural analogs. Molecular identification of SVCT2 was carried out with reverse transcription-polymerase chain reaction (RT-PCR). Uptake of [(14)C] AA was studied and found to be sodium, chloride, temperature, pH and energy dependent in all breast cancer cell lines. [(14)C] AA uptake was found to be saturable, with Km values of 53.85 ± 6.24, 49.69 ± 2.83 and 45.44 ± 3.16 μM and Vmax values of 18.45 ± 0.50, 32.50 ± 0.43 and 33.25 ± 0.53 pmol/min/mg protein, across MDA-MB231, T47D and ZR-75-1, respectively. The process is inhibited by structural analogs (l-AA and d-iso AA) but not by structurally unrelated substrates (glucose and PAHA). Ca(++)/calmodulin and protein kinase pathways appeared to play a crucial role in modulating AA uptake. A 626 bp band corresponding to a vitamin C transporter (SVCT2) based on the primer design was detected by RT-PCR analysis in all breast cancer cell lines. This research article describes AA uptake mechanism, kinetics, and regulation by sodium dependent vitamin C transporter (SVCT2) in MDA-MB231, T47D and ZR-75-1u2009cells. Also, MDA-MB231, T47D and ZR-75-1 cell lines can be utilized as a valuable in vitro model to investigate absorption and permeability of AA-conjugated chemotherapeutics.

Bitter Melon as a Therapy for Diabetes, Inflammation, and Cancer: a Panacea?

Natural products have been used for centuries for cures prevention, treatment, and cure of multiple diseases. Some dietary agents are present in multiple systems of medicines as proposed treatments for chronic and difficult to treat diseases. Once such natural product is Momordica charantia or bitter melon. Bitter melon is cultivated in multiple regions across the world, and various parts of the plant, such as fruit, leaves seed, etc. have been shown to possess medicinal properties in ancient literature. Over the last few decades, multiple well-structured scientific studies have been performed to study the effects of bitter melon in various diseases. Some of the properties for which bitter melon has been studied include: antioxidant, antidiabetic, anticancer, anti-inflammatory, antibacterial, antifungal, antiviral, anti-HIV, anthelmintic, hypotensive, anti-obesity, immuno-modulatory, antihyperlipidemic, hepato-protective, and neuro-protective activities. This review attempts to summarize the various literature findings regarding medicinal properties of bitter melon. With such strong scientific support on so many medicinal claims, bitter melon comes close to being considered a panacea.

Abstract 1893: Honokiol prevents colonic tumorigenesis and affects stem cell viability by affecting oncogenic YAP1 function

Background: Despite advances in early detection, colon cancer remains the second leading cause of death in the United States. We are focused on developing dietary prevention strategies. HNK (HNK) is a biphenolic compound that is used in the traditional Chinese Medicine for treating various ailments. The current study is designed to determine whether HNK affected colon cancer stem cells and to identify a mechanism. Method: Colon cancer (CRC) cell lines HCT116 and SW480 and normal colon epithelial cells were used in the study. Cell growth was measured by hexoseaminidase and clonogenicity assays. Apoptosis was determined by measuring caspase 3/7 activities. Colosphere formation assay and FACS sorting were used for stem cells. For in vivo effects, we used the AOM/DSS-induced colonic tumorigenesis model. Immunohistochemistry was determined for stem cell markers and Hippo signaling proteins. Results: HNK induced a significant dose-dependent inhibition of proliferation and colony formation of the two CRC lines, but induced apoptosis. HNK did not affect the normal cells. To demonstrate HNK effects on stem cells, we performed colosphere assays. HNK significantly reduced the number and size of colospheres, suggesting effects on stem cells. In addition, colon stem cell marker proteins DCLK1, LGR5, and CD44 were also decreased. Further proof was obtained by flow cytometry analyses, where HNK reduced the number of DCLK1+ cells. We next determined whether stem cell signaling is affected. For this, we looked at the Hippo signaling pathway, which is active in intestinal stem cells. The key effector protein of this pathway, YAP1 is also oncogenic in many cancer types. In the canonical Hippo signaling pathway, YAP1 function is inhibited. When YAP1 is phosphorylated at Ser127 by the action of upstream Mst1/2 and Lats1/2 kinases, it is sequestered in the cytoplasm where it is degraded, thereby inhibiting downstream gene expression. HNK significantly reduced YAP1 levels. Furthermore, HNK inhibited the expression of YAP interacting proteins TEAD1, TEAD2, and TEAD4. On the other hand, ectopic expression of the TEAD1 partially rescued the cells from HNK-mediated growth suppression. To determine the in vivo effect of HNK on AOM/DSS induced colonic tumorigenesis, HNK were oral gavaged at a dose of 5mg/kg bw for 24 weeks. HNK treatment significantly reduced the colonic tumor numbers and size. Western blot and immunohistochemistry analyses demonstrated significant inhibition in the expression of stem marker proteins, oncogenic YAP1 phosphorylation and TEAD1 in the HNK-treated AOM/DSS colonic tumor tissues. Conclusion: Together, these data suggest that HNK prevents colonic tumorigenesis that targets stem cells by inhibiting oncogenic YAP1 in Hippo signaling pathway. Citation Format: Dharmalingam Subramaniam, Sivapriya Ponnurangam, Deep Kwatra, Gaurav Kaushik, Prabhu Ramamoorthy, Satish Ramalingam, Ossama Tawfik, Scott J. Weir, Subhash Padhye, Dan A. Dixon, Shahid Umar, Roy A. Jensen, Shrikant Anant. Honokiol prevents colonic tumorigenesis and affects stem cell viability by affecting oncogenic YAP1 function. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1893. doi:10.1158/1538-7445.AM2015-1893

Abstract 5163: JMJD1a: A potential target for prevention and therapy in pancreatic cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnPurpose: Pancreatic cancer is the fourth leading cause of cancer related death in the United States. Therapeutic options for patients with advanced disease are time limited and non-curative. A growing body of evidence suggests that cancer stem cells (CSCs) within a solid tumors including in pancreatic cancer initiate and sustain tumor growth. Our preliminary data implicates Jumanji demethylases1a (JMJD1a) as a prime regulator of stem cell renewability for cancer progression. Hypoxia most prominently controls malignant properties of cancer cells by stimulating hypoxia inducible factor 1 (HIF1). HIF1 binds to its response elements (HREs) in the JMJD1a promoter and subsequently up-regulates JMJD1a. This could explain why hypoxia exacerbates malignancy. Therefore, we hypothesize that hypoxia induces JMJD1a that regulate self-renewability of CSCs, thereby promoting tumor initiation. Recently, two small molecules analogues of crocetinic acid, a carotenoid molecule isolated from saffron, have revealed to have potent antimitotic effects in pancreatic cancer models.nnExperimental Procedure: We have studied pancreatic CSCs during hypoxic and normoxic conditions allow to form multicellular spheroids called pancospheres and monitored expression of JMJD1a using western blots and immunohistochemistry on those CSCs. We also used shRNA to silence JMJD1a using lentiviral vectors in different pancreatic cancer cell lines.nnResults: JMJD1a was significantly overexpressed in human pancreatic cancer patient samples compared to their adjacent normal tissues. JMJD1a is overexpressed in pancreatic cancer cells and it is significantly reduced when it is knocked down through shRNA in those cell lines. The colony formation and migration assays were significantly reduced after knock-down of JMJD1a. Hypoxia stimulated pancospheres formation associated with concomitant overexpression of JMJD1a. Knock-down of JMJD1a using shRNA demonstrated significant reduction of pancospheres forming ability in both normoxic and hypoxic conditions. The demethylation of specific substrate of JMJD1a, H3-K9me2, was significantly increased by knock-down of JMJD1a in pancreatic cancer cells. Hypoxia significantly increases overexpression of cancer stem-cell and angiogenic markers in pancreatic cancer cells in vitro. Knock-down of JMJD1a significantly affected stem-cell specific markers in both hypoxia and normoxia. Treatment with gemcitabine did not affect in JMJD1a expression in those cell lines particularly during hypoxic conditions. Crocetinic acid and its analogues inhibited JMJD1a expression in both in vivo and in vitro pancreatic cancer models.nnConclusions: JMJD1a is overexpressed in pancreatic cancer and stimulates the self-renewability of pancospheres. In conclusion, JMJD1a is one of important factor for pancreatic cancer progression and could be a novel preventive and therapeutic target for pancreatic cancer.nnCitation Format: Kanagaraj Palaniyandi, Santanu Paul, Parthasarathy Rangarajan, Deep Kwatra, Satish Ramalingam, Dharmalingam Subramaniam, Tomoo Iwakuma, Subhash Padhye, Shrikant Anant, Animesh Dhar. JMJD1a: A potential target for prevention and therapy in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5163. doi:10.1158/1538-7445.AM2014-5163

Abstract 4553: Gedunin, a novel HSP-90 inhibitor, synergizes with cisplatin and paclitaxel to inhibit growth of chemoresistant ovarian cancer cell lines

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnHigh-grade serous ovarian cancer is the most lethal of all gynecological cancers. It is often not diagnosed until FIGO stage III or IV, at which point the 5-year survival rate is 15%. Although most patients initially respond to the standard of care, 70% of tumors reoccur. Of these, 70-90% are refractory to standard therapies used in the treatment of serous ovarian cancer, cisplatin and paclitaxel. These statistics reveal a need for novel therapeutics that target these tumors. Gedunin, a liminoid from the Neem tree (Azadirachta indica) has been identified as an HSP90-inhibitor. We tested whether gedunin affects the viability of five different ovarian cancer cell lines, ID8, ID8TaxR, A2870, C30 and CP70. We chose these cell lines because cisplatin (C30, CP70) and paclitaxel (ID8TaxR) resistant cells were developed from A2870 and ID8, respectively. Treatment with gedunin (0-30µM) inhibited growth of all five cell lines. In addition, combination indices revealed synergism between gedunin and the two chemotherapeutic agents. More importantly, synergism between gedunin and paclitaxel occurs even at doses (2.5µM for each) that do not have any effect on the cells when treated alone. We next determined the mechanism of gedunin action. Flow cytometry and immunofluorescence microscopy, demonstrated that gedunin induces mitotic arrest between metaphase and anaphase. This was confirmed by western blot analysis of cyclin protein levels. We also observed significant changes to expression of checkpoint kinase-1 (CHK1) and polo-like kinase-1 (PLK1) in the five cell lines. We propose that the misfolding and subsequent degradation of CHK1 and PLK1 leads to the observed mitotic halt, which eventually results in apoptosis. Following cell synchronization, gedunin-treated cells show decreased inhibitory phosphorylation (Y15) of CDK1 and increased levels of cyclin B1 compared to untreated cells. Moreover, immunofluorescence microscopy demonstrated increased monopolar spindle formation. Furthermore, gedunin treatment resulted in formation of double-strand breaks as observed by western blot analysis for gamma-H2AX. This was further verified by TUNEL staining. Finally, apoptosis was observed in gedunin treated cells as measured by increased Bcl-2 to Bax protein ratio and mitochondrial cytochrome c release. These data are in complete agreement with previous studies that show that PLK1 depletion causes spindle abnormalities, as well as increases gamma-H2AX and decreases BCL-2 protein levels. In conclusion, these data suggest that gedunin treatment results in premature mitosis followed by cell cycle arrest and apoptosis. Given that gedunin acts in synergism with both cisplatin and paclitaxel suggests that gedunin is a promising lead compound either alone or in combination with these compounds for the treatment of high-grade serous ovarian carcinoma.nnCitation Format: Jessica Johnson, Anand Venugopal, Deep Kwatra, Katherine Roby, Andrew Godwin, Shrikant Anant. Gedunin, a novel HSP-90 inhibitor, synergizes with cisplatin and paclitaxel to inhibit growth of chemoresistant ovarian cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4553. doi:10.1158/1538-7445.AM2014-4553

Abstract 1937: RBM3 overexpression increases β-catenin signaling activity to induce a cancer stem cell phenotype

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnColon cancer is the second leading cause of cancer related deaths in the US. We have previously demonstrated that the RNA binding protein RBM3 is oncogenic when overexpressed in NIH 3T3 cells. Furthermore, several studies have shown that RBM3 expression increases in high grade cancer compared to lower grade cancer or normal adjacent tissues. While a correlation between RBM3 expression and the progression of malignancies is apparent, the evidence implying a causative link is lacking. Here we investigate the effects of exogenous RBM3 overexpression on the phenotype of colon cancer cell lines HCT 116 and DLD-1. We developed cells with stable doxycycline (Dox) inducible RBM3 overexpression. Upon RBM3 overexpression, there was an increase in the percentage of Hoescht 33342 effluxing side population cells and spheroid formation capacity, both of which are populations with increased capacity to self-renew and differentiate. Additionally, we observed that RBM3 overexpression increases CD44 protein levels. These studies imply that RBM3 overexpression increases colon cancer stem cell phenotype. To elucidate the mechanism by which RBM3 overexpression increases the stem cell phenotype, we next investigated the β-catenin signaling pathway. The majority of colon cancers initiate their malignant transformation with an activating mutation of the Wnt/β-catenin signaling pathway which is critical in maintaining the stem cells within the intestinal epithelium. The small pool of cytoplasmic β-catenin is normally degraded, however, upon inhibition of the destruction complex, it translocates to the nucleus and induces transcriptional changes within the cell. RBM3 overexpression showed increase in both total and nuclear β-catenin in the two cell lines. To demonstrate directly that β-catenin is transcriptionally active, we used the TOPFlash luciferase reporter system. There was a significant increase in luciferase activity in RBM3 overexpressing cells confirming the increased nuclear β-catenin levels. Furthermore, there was increase in the expression of c-Myc, CD44 and LGR5 mRNA, all transcriptional targets of β-catenin. In previous studies, we have demonstrated that RBM3 induces the expression of cyclooxygenase-2 and interleukin-8, both of which can act through AKT to inhibit GSK3β, a member of the β-catenin destruction complex. Therefore, we next investigated effects of RBM3 overexpression on GSK3β activity. There was a significant increase in activating phosphorylation at Akt at Ser473, and inhibitory phosphorylation of GSK3β at Ser9. Additionally, β-catenin phosphorylation at Ser33/37/Thr41, targets of GSK3β was marked lower. Taken together, these data suggest that when overexpressed, RBM3 induces β-catenin signaling to increase stem cell features in colon cancer cells. Additionally, these data show a novel causative link between RBM3 levels and the progression of colon cancer.nnCitation Format: Anand Venugopal, Julia Balmaceda, Deep Kwatra, Dharmalingam Subramaniam, Shahid Umar, Shrikant Anant. RBM3 overexpression increases β-catenin signaling activity to induce a cancer stem cell phenotype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1937. doi:10.1158/1538-7445.AM2014-1937

Abstract 3734: Cancer stem cells: novel chemopreventive targets for pancreatic cancer.

Pancreatic cancer is the fourth leading cause of mortality in the United States and no significant treatment is currently available. Although an increasing number of therapeutic options exist for patients with advanced disease, their efficacy is time limited and non-curative. Presently approximately close to 60% of cancer patients in the United States are believed to utilize therapies derived from plants, herbs, flowers, or nutrients either exclusively or concurrently with traditional chemotherapy or radiation therapy. Recent evidence suggests the existence of a small population of tumorigenic stem cells responsible for tumor initiation, metastasis and resistance to chemotherapy and radiation. Identification of the regulatory mechanisms and signaling pathways involved in cancer stem cells (CSCs) will help in designing novel agents to target this refractory cell population in pancreatic cancers. We are currently investigating the mechanisms by which purified crocetinic acid, a carotenoid molecule isolated from saffron, inhibits growth of pancreatic cancer in vitro and in vivo models. Our studies demonstrate that the compound had significant cytotoxicity against pancreatic cancer cells in both a dose- and time-dependent manner. Pancreatic CSCs can be allowed to divide and grow in ultra-low binding tissue culture dishes to form multicellular spheroids called pancospheres. Treatment with purified crocetinic acid decreased the number and size of the primary and secondary pancospheres in a dose dependent manner, suggesting that crocetinic acid targets CSCs. To understand the mechanism of inhibition of pancospheres, the signaling pathways affected by crocetinic acid were dissected. Aberrant activation of Sonic Hedgehog signaling pathway has been associated with renewal of cancer stem cells, and in the development of several solid cancers. Sonic hedgehog (Shh) upon binding to its cognate receptor patched, allows smoothened to accumulate and activate Gli transcription factor. Treatment with crocetinic acid inhibited the expression of both Shh and smoothened in the pancreatic CSCs with concomitant reduction of the expression of a novel pancreatic CSC marker, DCLK-1 (Doublecortin Calcium/Calmodulin-Dependent Kinase-1). Furthermore, it inhibited the expression of patched-1 and Gli-1, downstream targets of the hedgehog signaling pathway. Crocetinic acid also inhibited tumor formation in pancreatic cancer in vivo xenograft models. Taken together, these data suggest that crocetinic acid effectively inhibits pancreatic CSCs by down regulating the sonic hedgehog pathway, thereby inhibiting tumorigenesis. Citation Format: Parthasarathy Rangarajan, Dharmalingam Subramaniam, Deep Kwatra, Shamima Islam, Kanagaraj Palaniyandi, Shrikant Anant, Animesh Dhar. Cancer stem cells: novel chemopreventive targets for pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3734. doi:10.1158/1538-7445.AM2013-3734