Molecular Mechanism of Capsaicin in Pancreatic Cancer Prevention and Therapy

SANJAY K. SRIVASTAVA 한의병리학회 2015 대한동의병리학회 학술대회논문집 Vol.2015 No.10

Capsaicin, the pungent alkaloid of red pepper has been studied extensively for its anti-inflammatory and anti-oxidant properties. Several studies have shown significant chemopreventive effects of capsaicin against several mutagens and carcinogens. Recent studies indicated that capsaicin suppresses cancer growth by inhibiting cell proliferation and induces apoptosis. Although, capsaicin is a TRPV1 agonist, various reports indicated that the anti-cancer effect of capsaicin is independent of TRPV1. Our studies have shown that capsaicin suppresses the growth of various pancreatic cancer cells and induces apoptotic death. Interestingly, effects of capsaicin were more specific to cancer cells with little or no toxicity towards normal human pancreatic cells. By modulating mitochondrial electron transport complexes, capsaicin generates reactive oxygen species and disrupts mitochondrial functions of pancreatic cancer cells, resulting in the release of cytochrome c into the cytosol and activating caspase-3 cascade. In addition, capsaicin reduces the levels of cellular antioxidants like glutathione, thioredoxin and superoxide dismutase. Capsaicin also inhibits beta catenin pathway and acetylates FOXO-1 through CBP, leading to apoptosis. Oral administration of 5mg/kg capsaicin suppresses the growth of various pancreatic tumor cells in xenograft and orthotopic tumor model. In addition, 10 p.p.m. capsaicin in diet for eight weeks significantly suppresses chronic pancreatitis and progression of PanIN-1 to high grade PanIN-2 and PanIN-3 lesions in KRas<SUP>G12D</SUP>/Pdx-1 mouse model of pancreatic cancer. When given in combination, capsaicin significantly potentiates the anti-tumor effects of gemcitabine. In conclusion, capsaicin targets multiple survival pathways in pancreatic cancer cells resulting in overall tumor growth suppression. [Supported by R01 grant CA129038 awarded by the National Cancer Institute. NIH]

Is Cervical Stabilization for All Cases of Chiari-I Malformation an Overkill? Evidence Speaks Louder Than Words!

Harsh Deora,Sanjay Behari,Jayesh Sardhara,Suyash Singh,Arun K. Srivastava 대한척추신경외과학회 2019 Neurospine Vol.16 No.2

Chiari I malformation is characterized by the downward displacement of cerebellar tonsils through the foramen magnum. While discussing the treatment options for Chiari I malformation, the points of focus include: (1) Has the well-established procedure of posterior fossa decompression become outdated and has been replaced by posterior C1–2 stabilization in every case? (2) In case posterior stabilization is required, should a C1–2 stabilization, rather than an occipitocervical fusion, be the only procedure recommended? The review of literature revealed that when there is bony instability like atlantoaxial dislocation (AAD), occipito-atlanto-axial facet joint asymmetry or basilar invagination (BI) associated with Chiari I malformation, one should address the anterior bony compression as well as perform stabilization. This takes care of the compromised canal at the foramen magnum and re-establishes the cerebrospinal fluid flow along the craniospinal axis; and also provides treatment for CVJ instability. In the cases with a pure Chiari I malformation without AAD or BI and with completely symmetrical C1–2 joints, however, posterior fossa decompression with or without duroplasty is sufficient to bring about neurological improvement. The latter subset of cases with pure Chiari I malformation have, thus, shown significant (>70%) rates of neurological improvement with posterior fossa decompression alone. A C1–2 posterior stabilization is a more stable construct due to the strong bony purchase provided by the C1–2 lateral masses and the short lever arm of the construct. However, in the cases with significant bleeding from paravertebral venous plexus; a very high BI, condylar hypoplasia and occipitalized atlas; gross C1–2 rotation or vertical C1–2 joints with unilateral C1 or C2 facet hypoplasia, as well as the presence of subaxial scoliosis; maldevelopment of the lateral masses and facet joints (as in very young patients); or, the artery lying just posterior to the C1–2 facet joint capsule (being endangered by the C1–2 stabilization procedure), it may be safer to perform an occipitocervical rather than a C1–2 fusion.

Caspase-9 as a therapeutic target for treating cancer

Kim, Bonglee,Srivastava, Sanjay K,Kim, Sung-Hoon Informa UK, Ltd. 2015 Expert opinion on therapeutic targets Vol.19 No.1

<P><B><I>Introduction:</I></B> Caspase-9 is the apoptotic initiator protease of the intrinsic or mitochondrial apoptotic pathway, which is activated at multi-protein activation platforms. Its activation is believed to involve homo-dimerization of the monomeric zymogens. It binds to the apoptosome to retain substantial catalytic activity. Variety of apoptotic stimuli can regulate caspase-9. However, the mechanism of action of various regulators of caspase-9 has not been summarized and compared yet. In this article, we elucidate the regulators of caspase-9 including microRNAs, natural compounds that are related to caspase-9 and ongoing clinical trials with caspase-9 to better understand the caspase-9 in suppressing cancer.</P><P><B><I>Areas covered:</I></B> In this study, the basic mechanism of apoptosis pathways, regulators of caspase-9 and the development of drugs to regulate caspase-9 are reviewed. Also, ongoing clinical trials for caspase-9 are discussed.</P><P><B><I>Expert opinion:</I></B> Apoptosis has crucial role in cancer, brain disease, aging and heart disease to name a few. Since caspase-9 is an initiator caspase of apoptosis, it is an important therapeutic target of various diseases related to apoptosis. Therefore, a deep understanding on the roles as well as regulators of caspase-9 is required to find more effective ways to conquer apoptosis-related diseases especially cancer.</P>

A Universal Craniometric Index for Establishing the Diagnosis of Basilar Invagination

Jayesh Sardhara,Sanjay Behari,Suyash Singh,Arun K. Srivastava,Gaurav Chauhan,Hira Lal,Kuntal K. Das,Kamlesh Singh Bhaisora,Anant Mehrotra,Prabhakar Mishra,Awadhesh K. Jaiswal 대한척추신경외과학회 2021 Neurospine Vol.18 No.1

Objective: The conventional criteria for defining the basilar invagination (BI) focus on the relationship of odontoid tip to basion and opisthion, landmarks that are intrinsically variable especially in presence of occipitalised atlas. A universal single reference line is proposed that helps in unequivocally establishing the diagnosis of BI, may be relevant in establishing both Goel types A and B BI, as well as in differentiating a ‘very high’ from ‘regular’ BI. Methods: Study design – case-control study. In 268 patients (group I with BI [n=89] including Goel type A BI [n=66], Goel type B BI [n=23], and group II controls [n=179]), the perpendicular distance between odontoid tip and line subtended between posterior tip of hard palate-internal occipital protuberance (P-IOP line) was measured. Logistic regression analysis determined factors influencing the proposed parameter (p<0.05). Results: In patients with a ‘very high’ BI (n=5), the odontoid tip intersected/or was above the P-IOP line. In patients with a ‘regular’ BI (n=84), the odontoid tip was 6.56±3.9mm below the P-IOP line; while in controls, this distance was 12.53±4.28 mm (p<0.01). In Goel type A BI, the distance was 7.01±3.78 mm and in type B BI, it was 5.07±4.19 mm (p=0.004). Receiver-operating characteristic curve analysis identified 9.0 mm (8.92–9.15 mm) as the cut-point for diagnosing BI using the odontoid tip-P-IOP line distance as reference. Conclusion: The odontoid tip either intersecting the P-IOP line (very high BI) or being <9 mm below the P-IOP line (Goel types A and B BI) is recommended as highly applicable criteria to establish the diagnosis of BI. This parameter may be useful in establishing the diagnosis in all varieties of BI.

Regulation of SIRT1/AMPK axis is critically involved in gallotannin-induced senescence and impaired autophagy leading to cell death in hepatocellular carcinoma cells

Kwon, Hee Young,Kim, Ju-Ha,Kim, Bonglee,Srivastava, Sanjay K.,Kim, Sung-Hoon Springer-Verlag 2018 Archives of toxicology Vol.92 No.1

<P>Hepatocellular carcinoma (HCC) is one of the most fatal malignancies with high mortality worldwide. Here the underlying antitumor mechanism of gallotannin was elucidated in HCC cells. Gallotannin suppressed viability and colony formation, increased subG(1) portion and also induced senescence via upregulation of p21, G(0)/G(1) arrest and higher SA-beta-gal activity in HepG2 and SK-Hep1 cells. However, pan-caspase inhibitor Z-VAD-FMK reversed the ability of gallotannin to activate caspase 3 at 48 h after treatment in two HCC cells. Of note, gallotannin also induced autophagic features by increasing LC3 punctae, LC3B-II conversion, autophagic vacuoles and decreasing the expression of Beclin1 in two HCC cells. Furthermore, autophagy flux assay using GFP-mRFP-LC3 plasmid revealed increased yellowish color and late autophagy inhibitor CQ or NH4Cl enhanced cytotoxicity, LC3B-II conversion, and LC3 punctae in gallotannin-treated HepG2 and SK-Hep1 cells compared to early autophagy inhibitor 3-MA or wortmannin. Interestingly, gallotannin attenuated the expression of SIRT1 and mTOR and activated phosphorylation of AMPK in two HCC cells. Furthermore, AMPK activator AICAR significantly enhanced SA-beta-gal activity and antiproliferation induced by gallotannin, while AMPK inhibitor compound C did not in two HCC cells. Consistently, LC3B-II conversion by gallotannin was not shown in AMPK alpha 1(-/-) MEF cells compared to WT AMPK(+/+) MEF cells. Consistently, gallotannin reduced in vivo growth of HepG2 cells implanted in NCr nude mice along with decreased expression of PCNA and SIRT1 and increased AMPK alpha 1 and TUNEL. Overall, these findings highlight evidence that regulation of SIRT1/AMPK is critically involved in gallotannin-induced senescence and impaired autophagy leading to cell death in HCC cells.</P>

Zinc finger protein 746 promotes colorectal cancer progression via c-Myc stability mediated by glycogen synthase kinase 3β and F-box and WD repeat domain-containing 7

Jung, Ji Hoon,Jung, Deok-Beom,Kim, Hyunseok,Lee, Hyemin,Kang, Shi-Eun,Srivastava, Sanjay K.,Yun, Miyong,Kim, Sung-Hoon Nature Publishing Group UK 2018 Oncogene Vol.37 No.27

<P>To elucidate the underlying oncogenic mechanism of zinc finger protein 746 (ZNF746), current study was conducted in colorectal cancers (CRCs). Herein, ZNF746 was overexpressed in HCT116, SW620, and SW480 cells, which was supported by CRC tissue microarray and TCGA analysis. Also, DNA microarray revealed the differentially expressed gene profile particularly related to cell cycle genes and c-Myc in ZNF746 depleted HCT116 cells. Furthermore, ZNF746 enhanced the stability of c-Myc via their direct binding through nuclear colocalization by immunoprecipitation and immunofluorescence, while ZNF746 and c-Myc exist mainly in nucleoplasm. Conversely, ZNF746 depletion attenuated phosphorylation of c-Myc (S62) and glycogen synthase kinase 3 beta (GSK3 beta) (S9) and also activated p-c-Myc (T58), which was reversed by GSK3 inhibitors such as SB-216763 and Enza. Also, c-Myc degradation by ZNF746 depletion was blocked by knockdown of F-box/WD repeat-containing protein 7 (FBW7) ubiquitin ligase or proteosomal inhibitor MG132. Additionally, the growth of ZNF746 depleted HCT116 cancer cells was retarded with decreased expression of ZNF746 and c-Myc. Overall, these findings suggest that ZNF746 promotes CRC progression via c-Myc stability mediated by GSK3 and FBW7.</P>

A derivative of epigallocatechin-3-gallate induces apoptosis via SHP-1-mediated suppression of BCR-ABL and STAT3 signalling in chronic myelogenous leukaemia : EGCG-MP effectively induces apoptosis in CML

Jung, Ji Hoon,Yun, Miyong,Choo, Eun-Jeong,Kim, Sun-Hee,Jeong, Myoung-Seok,Jung, Deok-Beom,Lee, Hyemin,Kim, Eun-Ok,Kato, Nobuo,Kim, Bonglee,Srivastava, Sanjay K,Kaihatsu, Kunihiro,Kim, Sung-Hoon Wiley (Blackwell Publishing) 2015 British journal of pharmacology Vol.172 No.14