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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Fosbretabulin (combretastatin-A4 phosphate or CA4P) is a prodrug of combretastatin-A4 developed by (the then) biotech company OXiGENE Inc. It exerts its antitumor activity through two mechanisms. First, in a similar manner to the parent combretastatin A4, it provides a direct anti-vascular effect on established tumor blood vessels by rapidly and selectively interacting with the colchicine-binding site of β-tubulin. This destabilizes the microtubules and produces changes in the three-dimensional shape of immature endothelial cells inadequately protected by pericytes. The blood flow through tumor blood vessels is thus reduced, leading to ischemia and necrosis of cells within the tumor core. The second effect involves disruption of the engagement of vascular endothelial-cadherin (VE-cadherin), the endothelial cell-specific junctional molecule in the VE-cadherin/β-catenin/Akt signaling pathway resulting in inhibition of endothelial cell migration and capillary tube formation. As a result of both mechanisms, fosbretabulin causes collapse of the tumor vasculature resulting in reduced tumor blood flow and ischemic necrosis of tumor tissue. However, studies in preclinical animal models showed that, after treatment with fosbretabulin, tumor regrowth occurred on the peripheral rim of the tumor via recruitment of circulating endothelial progenitor cells. This suggested that a combination of fosbretabulin with an anti-VEGF antibody (e.g., bevacizumab) should reduce re-vascularization of the surviving tumor rim, thus significantly increasing antitumor activity.
Genetic Engineering of Clostridial Strains for Cancer Therapy
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Maria Zygouropoulou, Aleksandra Kubiak, Adam V. Patterson, Nigel P. Minton
A few years later, Theys and colleagues engineered two different strains of C. acetobutylicum (DSM 792, NI4082) to express and secrete the same protein. The recombinant spores were delivered to WAG/Rij rats bearing subcutaneous rhabdomyosarcomas. CD activity could be detected in 10/18 tumors treated with strain DSM 792 and 4/6 tumors treated with strain NI4082, while no activity was detected in healthy tissues. When strain NI4082 was combined with Combretastatin A-4 phosphate (CombreAp), proven to promote vascular collapse and amplify hypoxia, the incidence of CD activity in tumors increased to 100% (6/6 tumors). Most importantly, it was shown that the efficiency of conversion of 5-FC to 5-FU achieved could enable clinically relevant sensitization of tumors to radiotherapy [38, 46].
Combined radiotherapy and chemotherapy
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Vincent Grégoire, Jean-Pascal Machiels, Michael Baumann
As an opposite paradigm, angiogenesis being an essential component of tumour growth, the use of vascular disrupting agent, which would further enhance hypoxia leading to anoxia and cell death, has been widely tested with radiation. Combretastatin A4 phosphate (CA4P) is the lead compound of this class of agents and has been shown to increase tumour hypoxia and induce rapid necrosis in the centre of the tumour leaving a rim of viable cells at the periphery. When combined with radiation, providing an appropriate timing and schedule of administration was used, an enhanced effect could be observed after both single and fractionated doses of radiation (30).
Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Moran Sun, Minghua Yuan, Yingying Kang, Jinling Qin, Yixin Zhang, Yongtao Duan, Longfei Wang, Yongfang Yao
The most studied group of VDAs is microtubule-destabilizing agents that interact at the colchicine-binding site of the αβ-tubulin dimer5. Compared with other site binders, colchicine-site binders have several advantages including simpler structure, low toxicity, improved aqueous solubility and fewer issues of multidrug resistance6. The normal function of endothelial cells, including movement, invasion, attachment, arrangement, and proliferation, is highly dependent on the tubulin cytoskeleton. It has been shown that endothelial cells of immature vasculature have a less developed actin cytoskeleton and are therefore more sensitive to the effects of VDAs. Consequently, the vascular targeting properties of VDAs were invariably linked to the microtubule-binding properties of the compound. In general, colchicine-site binders have anti-angiogenesis or disrupting established tumour vasculature effects or both7. Combretastatin A4(CA-4), a representative colchicine-site binder, exhibit prominent anti-angiogenic property within solid tumour, suggesting that this class of compounds could target the tumour vasculature and ultimately lead to tumour necrosis (Figure 1)8. The water-soluble phosphate prodrug CA-4P (Zybrestat TM) has been approved as an orphan drug for anaplastic thyroid cancer treatment by FDA9. However, Z-natural stilbene compound CA-4 is prone to isomerise to the more stable E-isomer during storage and administration, which displayed a dramatically reduced activity.
Combretastatin-based compounds with therapeutic characteristics: a patent review
Published in Expert Opinion on Therapeutic Patents, 2019
Lalit Mohan Nainwal, Mohammad Mumtaz Alam, Mohammad Shaquiquzzaman, Akranth Marella, Ahmed Kamal
Combretastatins (Combretastatin A-4) are also clinically evaluated because they are potent vascular targeting agents or vascular disruptors (destroy the tumor blood vasculature) hence cut down the oxygen and nutrients supply to tumor cells that lead to tumor cell death [13]. Several other mechanisms by which combretastatins exert their anticancer effects have been established which include induction of mitosis independent apoptosis, hypoxia, anti-angiogenic, antimetastasis, and antimigration action, that contribute to their anticancer activity [14]. Apart from anticancer activity, anti-angiogenesis effect of combretastatins (like combretastatin A-4) extended their therapeutic application in other diseases which shows abnormal neovascularization like in retinal neovascularization and choroidal neovascularization of eyes [15–17]. Although several reviews and book chapters on tubulin inhibitors and combretastatins are published in the literature [6,18–28], but no patent review on combretastatins has been published yet. Here, in this review, we are mainly focusing on patents filed between 2008 and 2018 related to therapeutic applications and properties of combretastatin derivatives that are summarized at glance in Table 1.
Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Tarek S. Ibrahim, Mohamed M. Hawwas, Azizah M. Malebari, Ehab S. Taher, Abdelsattar M. Omar, Thikryat Neamatallah, Zakaria K. Abdel-Samii, Martin K. Safo, Yaseen A. M. M. Elshaier
In this study, we designed, synthesised and evaluated two classes of novel quinoline compounds combretastatin A-4 derivatives as potential inhibitors of tubulin polymerisation. Several other studies have also reported derivatisation of the CA-4 pharmacophore with varying success27–32. Unlike the previous compounds, we for the first time introduced a chalcone system, including oxazolones and imidazolones to the cis bond of CA-4 to give more rigidity to the required active conformation. The chalcone system is well known for its anticancer activities. Our design also kept the essential natural trimethoxyphenyl pharmacophore (found in CA-4), while varying the electronic substituents effect on the quinolyl moiety (ring B) that were expected to enhance the potency of the compounds. Most of the compounds showed significant and, in some instances, comparable antiproliferative activities against different cancer cell lines as the previously studied combretastatin A-4 compound, CA-4. One of the most promising compound 12c showed potent anti-proliferative activities against HL-60, MCF-7, HCT-116 and HeLA cancer cell lines with IC50 values of 0.019, 0.010, 0.022 and 0.042 µM, respectively, and simultaneously low cytotoxicity towards MCF-10A non-cancer cells. The microtubule polymerisation inhibitory effect of 12c was confirmed with an in vitro tubulin polymerisation and colchicine inhibition assays. Compound 12c effectively block the G2/M phase at the cell cycle and induce MCF-7 cell apoptosis together with significant change of Bax/Bcl expression ratio indicating involvement of mitochondrial apoptosis pathway. Further cellular mechanistic studies confirmed that 12c inhibited MCF-7 cell migration and colony formation. In conclusion, these results highlight our novel quinoline compounds and particularly 12c as promising anti-tubulin agent for the treatment of MCF-7 breast cancer cells. Moreover, the results point to a direction for rational development of potent tubulin polymerisation inhibitors for the treatment of cancer.