Angiogenesis, necessary for tumor growth involves cell proliferation and directed migration. Thus, there is clearly a crucial role of cytoskeletal microtubule (MT) dynamics in angiogenesis;linking perturbations of MT dynamics to Inhibition of tumor angiogeneisis. Our preliminary data strongly suggest that a semisynthetic tubulin-binding anticancer agent,(S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]-dioxolo[4,5- g]-iso-quinolin-5-yl)-6,7-dimethoxylsobenzofuran-1(3H)-one (EM011), has potent antiangiogenic activity (based upon NCI-DTP antiangiogenic drug screen). Our hypothesis is that EM011 will serve as an effective anticancer agent since it can target the MT cytoskeleton without causing any gross effects (over- or depolymerization of MTs) with concomitant antiangiogenic effects.
The specific aims for the mentored phase were:
Aim 1. Evaluation of the antiangiogenic efficacy of EM011.
Aim 2. Determination of EM011's effect on the dynamic instability of MTs, HIF-1alpha expression and transactivation of downstream targets such as VEGF. We have successfully accomplished the proposed research in the K99 phase. Based upon the nontoxic attributes of EM011, we rationalize that combination of EM011 with other angiogenic inhibitors that function through independent mechanisms but show toxicity at their maximum tolerated doses (MTDs), presents a unique opportunity to reduce their doses to maximize therapeutic outcomes with decreased toxicity. The ROO phase of the project will focus on 2 aims:
Aim 3. Investigation of potential synergistic antiproliferative and antiangiogenic effects of combinations of EM011 and ZD6474 (a tyrosine kinase inhibitor), or thalidomide (endothelial cell proliferation inhibitor) in breast (MDA-MB-231) and prostate (PC-3) cancer cells.
Aim 4. Determination of the In vivo efficacy of EM011 and its synergistic combinations with ZD6474 or thalidomide, as inhibitors of experimental primary and metastatic breast and prostate cancers in real-time using non-invasive bioluminescent imaging.

Public Health Relevance

As a practical and translational approach, the long-range goal of these studies would be to define and establish the usefulness of EM011 alone, and its synergistic combinations with other drugs, for remission of human breast and prostate cancers without compromising the quality of life.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgia State University
Schools of Arts and Sciences
United States
Zip Code
van Waardenburg, Robert C A M (2016) Tyrosyl-DNA Phosphodiesterase I a critical survival factor for neuronal development and homeostasis. J Neurol Neuromedicine 1:25-29
Mishra, Ram C; Gundala, Sushma R; Karna, Prasanthi et al. (2015) Design, synthesis and biological evaluation of di-substituted noscapine analogs as potent and microtubule-targeted anticancer agents. Bioorg Med Chem Lett 25:2133-40
Yang, Chunhua; Gundala, Sushma Reddy; Mukkavilli, Rao et al. (2015) Synergistic interactions among flavonoids and acetogenins in Graviola (Annona muricata) leaves confer protection against prostate cancer. Carcinogenesis 36:656-65
Mukkavilli, Rao; Gundala, Sushma R; Yang, Chunhua et al. (2015) Noscapine recirculates enterohepatically and induces self-clearance. Eur J Pharm Sci 77:90-9
Ogden, Angela; Rida, Padmashree C G; Reid, Michelle D et al. (2014) Interphase microtubules: chief casualties in the war on cancer? Drug Discov Today 19:824-9
Pawar, Shrikant; Donthamsetty, Shashikiran; Pannu, Vaishali et al. (2014) KIFCI, a novel putative prognostic biomarker for ovarian adenocarcinomas: delineating protein interaction networks and signaling circuitries. J Ovarian Res 7:53
Henary, Maged; Narayana, Lakshminarayana; Ahad, Shazia et al. (2014) Novel third-generation water-soluble noscapine analogs as superior microtubule-interfering agents with enhanced antiproliferative activity. Biochem Pharmacol 92:192-205
Pannu, V; Rida, P C G; Celik, B et al. (2014) Centrosome-declustering drugs mediate a two-pronged attack on interphase and mitosis in supercentrosomal cancer cells. Cell Death Dis 5:e1538
Gundala, Sushma Reddy; Yang, Chunhua; Mukkavilli, Rao et al. (2014) Hydroxychavicol, a betel leaf component, inhibits prostate cancer through ROS-driven DNA damage and apoptosis. Toxicol Appl Pharmacol 280:86-96
Gundala, Sushma R; Aneja, Ritu (2014) Piper betel leaf: a reservoir of potential xenohormetic nutraceuticals with cancer-fighting properties. Cancer Prev Res (Phila) 7:477-86

Showing the most recent 10 out of 30 publications