Cancer Cell Targeting

Cancer Cell Targeting

Solute Carriers (SLCs) as well as ATP-binding cassette (ABC) transporters, so-called efflux transporters are over-expressed in many different types of cancer cells and in solid tumors. Thus, SCLs can be utilized for cancer cell-targeted selective drug delivery or to inhibit and starve the cancer cell from essential nutrients. ABC transporters, on the other hand, have a crucial role in cancer biology and more importantly in chemoresistance, as they can pump a wide range of chemotherapeutics out of the cancer cells and thereby reduce the efficacy of these anti-cancer drugs. Therefore, targeting efflux transporter inhibitors selectively into the cancer cell may offer a potential alternative to improve the efficacy of chemotherapeutics.

The main aim of our research group is to study:
1. LAT1 as a Selective Carrier of Chemothrerapeutics or Efflux Transporter Inhibitors
2. Other Transporters as Novel Carriers of Anti-Cancer Agents
3. LAT1 Inhibition to Prevent Cancer Cell Proliferation

By inhibiting L-type amino acid transporter 1 (LAT1) that is over-expressed in several cancer types, protein synthesis and cell proliferation and can be hindered. We have reported that this inhibition is very effective alone, but it can also potentiate the effects of several other anti-cancer agents. This is expected to improve not only the efficacy but also the safety of chemotherapy, as the amounts of used anti-cancer agents can be reduced. More importantly, a selective inhibitor can be developed also as a novel diagnostic agent and be studied as a modifying tool for brain amino acid homeostasis. Although we are currently studying mainly LAT1 as a carrier and a target protein, we are constantly looking up also other potential SCLs, such as organic cation transporters (OCTs)in the delivery of metformin derivatives.

Selected Publications

LAT1-Utilizing Prodrugs of Chemotherapeutics or Efflux Transporter Inhibitors

Huttunen J.; Gynther, M.; Huttunen, K. M. Targeted Efflux Transporter Inhibitors – A Solution to Improve Poor Cellular Accumulation of Anti-cancer Agents. International Journal of Pharmaceutics, 2018, 550, 278-289. https://doi.org/10.1016/j.ijpharm.2018.08.047

Montaser, A.; Markowicz-Piasecka, M.; Sikora, J.; Jalkanen, J.; Huttunen, K. M. L-Type Amino acid Transporter 1 (LAT1)-Utilizing Efflux Transporter Inhibitors Can Improve the Brain Uptake and Apoptosis-Inducing Effects of Vinblastine in Cancer Cells. International Journal of Pharmaceutics, 2020, 586, 119585. https://doi.org/10.1016/j.ijpharm.2020.119585

 

Other Transporters as Novel Anti-Cancer Carriers 

Markowicz-Piasecka, M.; Sadowski, K.; Huttunen, J.; Sikora, J.; Huttunen, K.M. Incorporation of Sulfonamide Moiety into Biguanide Scaffold Results in Apoptosis Induction and Cell Cycle Arrest in MCF-7 Breast Cancer Cells. International Journal of Molecular Sciences, 2021, 22(11): 5642. https://doi.org/10.3390/ijms22115642

Markowicz-Piasecka, M.; Komeil, I.; Huttunen, J.; Sikora, J.; Huttunen, K. M. Effective cellular transport of ortho-halogenated sulfonamide derivatives of metformin is related with improved antiproliferative activity and apoptosis induction in MCF-7 cells. International Journal of Molecular Sciences, 2020, 21, 2389-2417. https://doi.org/10.1016/j.bioorg.2019.03.036

Markowicz-Piasecka M, Huttunen J, Sikora J, Huttunen KM. Sulfenamide derivatives can improve transporter-mediated cellular uptake of metformin and induce cytotoxicity in human breast adenocarcinoma cell lines. Bioorganic Chemistry, 2019, 87, 321-334. http://doi.org/10.1016/j.bioorg.2019.03.036

 

Inhibitors of LAT1 as a Novel Anti-Cancer Agents

Huttunen, K. M.; Gynther, M.; Huttunen, J.; Puris, E.; Spicer, J. A.; Denny, W. A. A Selective and Slowly Reversible Inhibitor of L-Type Amino Acid Transporter 1 (LAT1) Potentiates Antiproliferative Drug Efficacy in Cancer Cells. Journal of Medicinal Chemistry, 2016, 59 (12), 5740-5751. http://doi.org/10.1021/acs.jmedchem.6b00190

Markowicz-Piasecka, M.; Huttunen, J.; Montaser, A.; Huttunen, K. M.  Hemocompatible LAT1-inhibitor Can Induce Apoptosis in Cancer Cells Without Affecting Brain Amino Acid Homeostasis. Apoptosis, 2020, 25(5), 426-440. http://doi.org/10.1007/s10495-020-01603-7