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Project Group Anticancer & Targeting

The project group Anticancer Agents and Targeting focusses, in general, on the identification, characterization and synthesis of bioactive natural compounds and improved synthetic derivatives (based on over 20,000 compounds from plants or fungi and more than 3,000 plant extracts; see RG Data & Resources). For those screenings, our group has implemented a broad panel of cell biological (human and mouse cell lines), biochemical and molecular biology methods (see Fig. 1). Chemoinformatic and molecular modeling approaches are used in cooperation with the Computational Chemistry group of NWC. 

Figure 1: In vitro screening capabilities of the project group based on tumor and non-tumor cell lines (mostly human). The goal is to identify and characterize promising biological activities of natural compounds or synthetic analogues thereof.

The goal is to identify those chemical structures of natural origin that permit promising effects with respect to human health and well-being or even plant stress tolerance (e.g. PARP enzyme modulators, v.i.). For the most promising compounds we are searching for structurally related derivatives, but even more importantly we design and synthesize non-natural analogues with improved access and pharmacological parameters (e.g. tubugi derivatives of tubulysin toxins, see Fig. 2).



Figure 2:
Tubulysins, e.g. tubulysin D, are extremely potent cytotoxic compounds naturally synthesized from soil Myxobacteria that destroy the cells’ tubulin cytosceletal network and act in up to low picomolar concentrations. Tubugi-1 and derivatives thereof are synthetic tubulysin analogues with adjustable toxicities, functionali-ties and improved stability that are synthesized on solid and in liquid phase, respectively, by the NWC department. Therefore, tubugi derivatives are ideal payloads for targeted drug delivery applications. They also have added positive properties on the immune system and cause atypical apoptosis.

Especially for highly potent (e.g. cytotoxic) compounds it is advantagious or even necessary to include targeted therapy approaches in order to specifically address diseased tissue. I.e. the design, synthesis and testing of targeting vehicles helps to enhance the specificity and selectivity of the active compounds and consequently shall reduce undesired adverse effects. Such approaches include the use of peptide drug conjugates (PDCs), antibody-drug-conjugates (ADCs), nanoparticle delivery, or small molecule based targeting.

Moreover, a general part of our work is to shed light on the biological modes of action of the compounds under investigation, whereby those compounds with non-classical modes are of highest interest, e.g. compounds that might be able to reprogram tumor cells instead of simply kill them, or which make tumor stem cells or resting cells accessible for attack by our toxins. In this context we especially look at the influence of plant natural products as adjuvants or boosters of chemotherapy (see Fig. 3).



Figure 3:
Isoxanthohumol (IXN), a prenylflavonoid from hops, was found and proven to permit anti-proliferative activity against B16 melanoma tumor cells in vitro as well as in vivo in C57BL/6 mouse xenograft. Furthermore, IXN was able to strongly sensitize the melanoma tumors for the treatment with the well-established chemotherapeuticum and plant natural product paclitaxel, indicating an adjuvant and synergistic mode of action (Krajnović, T. et al., Pharmacol. Res. 2016, 105, 62-73: Versatile antitumor potential of isoxanthohumol: En-hancement of paclitaxel activity in vivo).

Hence, the focus of most of the current projects lies on anti-cancer and anti-inflammatory compound effects:

  • Design, synthesis and testing of targeting vehicles of the most promising compounds screened for targeted therapy approaches
  • Metabolomic fingerprinting of cancer cell lines under treatments
  • Screening for naturally-derived and synthetic PARP inhibitors (for plant drought stress and anti-cancer applications; see Fig. 4)
  • Screening for natural compounds acting as synergistic adjuvants of established anti-cancer therapies (e.g. isoxanthohumol enhancing paclitaxel activity; see Fig. 3)
  • Screening for novel plant-derived compounds for the treatment of elderly people with chronic blood diseases
Figure 4: Several factors have the capability to introduce a single strand break (SSB) in DNA. The SSB are recognized by a protein called poly-ADP-ribose-polymerase (PARP) which marks the damaged DNA, histones and even itself, by addition of poly-ADP tails. The inhibition of PARP by using PARP inhibitors (PARPi), as for instance Olaparib (clinically approved PARPi), leads to the inhibition of DNA repair. The progress of damaged DNA replication causes either double strand breaks (DSB) or the collapse of the DNA replication fork. This type of damage is recognized and repaired by another family of proteins known as BRCA. Several cancer types showed deficiency in BRCA such as breast and ovarian cancer. Therefore, PARPi could serve as promising (additional) drugs for the targeted teatment of BRCA-deficient cancers.

Moreover, PARP enzymes are also known from plants, where these enzymes have been described to be involved not only in DNA repair but to modulate also the plants’ sensitivity against several abiotic stress factors, especially drought stress. In plants, PARP inhibitors are discussed to improve the resistance against those stress factors, enhancing the plants yield under suboptimal conditions. See also our project group on phytoeffectors.

Technical Resources

Our laboratory is well equipped with a high-end BD FACSAria™ III flow cytometer (Becton Dickinson), Pipetmax (Gilson), an EVOS FL imaging system (Thermo Fisher Scientific), a SpectraMax M5 multi-mode plate reader (Molecular Devices), a Countess® II automated cell counter (Thermo Fisher Scientific), western blot capabilities, Lemnatec Scanalyser (Lemna-tec GmbH), CO2 incubators, biological safety cabinets (class I and II), cryogenic cell storage facilities and more.

This page was last modified on 29.06.2020.

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