Abstract 1667: Design and development of a parthenolide-combretastatin hybrid drug (VA-11) with highly potent antimicrotubule and NF-kB inhibitory activities

Abstract

Abstract Given the molecular complexity of cancers, their extreme heterogeneity and innate or acquired resistance to anticancer drugs, there is an increasing need for hybrid drugs that can effectively and simultaneously impact two or more targets triggering multiple cytocidal events in synergy to obtain superior chemo-sensitivities and prevent tumor resistance. Therefore, we developed a hybrid drug by combining the NF-kb inhibiting and oxidative stress-inducing parthenolide, a sesquiterpene lactone derived from the plant feverfew with the combretastatin A4 (CA4), a potent antimicrotubule and anti-angiogenesis agent. These hybrid compounds were synthesized by incorporating the α-methylene-γ-butyrolactone, an active component of parthenolide into the CA4 by replacing the unstable cis-double bond. The structural design of these hybrid compounds preserved the CA4 nucleus in the cis-configuration and prevented its isomerization into its biologically inactive trans-form. VA-11 was the highly potent among the different compounds prepared in specifically killing the tumor cells of various human cancer types at nano molar range. These included the colon (HT29, HCT116, SW640), breast (MDA-MB-231, SK-BR-3, MCF7), lung (A549, H1299, H460), brain (SF188, GBM10, GBM6, DAOY, T98G, U87MG) and pancreas (MIA-PaCa-2, PANC-1, BxPC-3). Particularly significant was that VA-11 was 10 times more potent than CA4 against the HT29 colon cancer cells. Various biochemical and immunocytochemical assays revealed that VA-11 retained the microtubule-disrupting effects of CA4, including microtubule depolymerization, the formation of aberrant mitotic spindles, and G2/M phase arrest. The hybrid drug also inhibited the polymerization of purified tubulins in vitro. Furthermore, VA-11 potently inhibited the formation of tubes in three-dimensional cultures of the HUVEC (Human umbilical Vein Cells), drastically decreasing the tube length and junctions at 1 μM concentration. The cancer cell migration /invasion, determined by transwell assays were also inhibited, and the inhibition was accompanied by increased E-cadherin levels through NF-κB/Snail pathway. Further, VA-11 inhibited the NF-κB activation, IκBα degradation, and IκB Kinase complex activity in HT29 cells tested in this study. VA-11 pretreatment significantly inhibited the IL-8 secretion induced by the cytokines such as LPS and/or TNF. These studies confirmed that VA-11 inhibits IκB kinase, resulting in stabilization of cytoplasmic IκBα, which in turn leads to inhibition of NF-κB translocation and attenuation of subsequent inflammatory responses and drug resistance. In conclusion, our results indicate that VA-11 represents a new prototype chemo drug with multiple mechanisms of action. Such hybrid anticancer drugs merit further development (supported by CPRIT grants RP130266 and RP170207 to KSS). Citation Format: Viswanath Arutla, Surendra R. Punganuru, Hanumantharao Madala, Kalkunte S. Srivenugopal. Design and development of a parthenolide-combretastatin hybrid drug (VA-11) with highly potent antimicrotubule and NF-kB inhibitory activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1667.