Leonard Lothstein, Ph.D.
Associate Professor
Laboratory of Experimental Cancer Therapeutic
Room 411 Crowe Research Building
Phone: (901) 448-3334
FAX: (901) 448-7206
Email: llothstein@utmem.edu
A.B., Bowdoin College, Brunswick, ME (Biology) - 1976
Ph.D., Vanderbilt University, Nashville, TN (Molecular Biology) - 1983
Post-doctoral Fellow, Laboratory of RNA Synthesis, Memorial Sloan-Kettering
Cancer Center, NY.
Post-doctoral Fellow, Dept. of Molecular Pharmacology and the Belfer
Institute for Advanced Biomedical Studies, Albert Einstein College
of Medicine, NY.
Current Positions:
Associate Professor of Pharmacology (College of Medicine)
Associate Professor of Pharmaceutical Sciences (College of Pharmacy)
Program Leader, Developmental Therapeutics/Clinical Research, The UT Cancer Institute
Director, The Center for Anticancer Drug Research (http://www.utmem.edu/pharmacology/reserach_cancer.html)
Research Interest:
Design, development, and mechanistic analysis of
anthracycline PKC activators Anti-tumor drug targeting of apoptotic signaling
pathways.
Cellular resistance to anti-tumor drugs
Cardioprotective signaling by novel anti-tumor agents
Active Research Projects:
Development and mechanistic analysis of a novel class
of 14-O-acyl anthracycline congeners that are functionally distinct from
the conventional anthracycline anti-tumor agent, doxorubicin (DOX).
Lead compounds of this group (AD 198 and AD 445) bind to the C1b regulatory domain of the C family of protein kinases (PKC) and induce kinase activation. However, unlike other PKC activators, such as phorbol esters, AD 198 and AD 445 trigger rapid apoptotic cell death in a wide variety of tumor cells through PKC-d activation and via a pathway that circumvents the anti-apoptotic/proliferative effects of Bcl-2, Bcl-XL, Bcr-Abl fusion tyrosine kinase, NF-kB, and p53 dysfunction. The precise mechanisms of action is currently under investigation. Recent studies have so far revealed that AD 198 and AD 445 trigger mitochondrial membrane depolarization and cytochrome c release through a novel mechanism that is independent of mitochondrial permeability transition pore involvement. In at least one tumor line, AD 198-induced apoptosis occurs through PKC-delta-mediated activation of phospholipid scramblase 3, which in turn causes the translocation of cardiolipin from the inner to outer mitochondrial membrane and increases pro-apoptotic tBid binding. Ongoing studies aim at identifying the mechanistic differences between the 14-O-acylanthracycline and phorbol esters, elucidating potential synergistic effects between the 14-O-acylanthracycline PKC activators and other new targeted anti-tumor agents, and the eventual clinical development of the 14-O-acylanthracyclines.
Cardioprotection by AD 198 and AD 445.
The potential therapeutic importance of AD 198 is reinforced by the absence of chronic, dose dependent cardiotoxicity, which is a serious clinical adverse effect of doxorubicin. We have determined that AD 198 is non-cardiotoxic despite its ability to generate ROS to an extent similar to doxorubicin. Further, AD 198 has a potent cardioprotective effect on rodent hearts through the direct activation of PKC-e, a critical component in cardioprotective signaling that inhibits myocardial damage during ischemia. Initial studies of the combined effects of trastuzumab and AD 198 on mouse cardiomyocytes suggest that low-dose AD 198 inhibits trastuzumab-induced ATP depletion and, thus, may be able to protect hearts from the cardiotoxic effects of trastuzumab.
Synergistic effects of 14-O-acylanthracyclines with ionizing radiation.
We have also demonstrated that other members of this novel group of
anthracyclines (N-trifluoroacetyladriamycin-14-valerate; AD
32, Valstar®, and N-trifluoroacetyladriamycin-14-pivalate;
AD 36) synergize at sub-cytotoxic doses with low-dose ionizing radiation
in head/neck squamous carcinoma cells. The combined effect is persistent
G2/M blockade without detectable DNA fragmentation. Since AD 32
and AD 36, like AD 198, localize almost exclusively in the cytoplasm,
we are currently investigating the combined effect of AD 32, AD 36 and
IR on the cytoplasmic components of G2/M regulation.
Barrett CM, Roaten JB, Lewis FL, Sweatman TW, Israel M, Lothstein L. Drug-induced modulation of protein kinase C (PKC) correlates with circumvention of Bcl-2-mediated inhibition of apoptosis. Molec. Cancer Ther. 1:469-481, 2002.
Roaten JB, Kazanietz MG, Caloca MJ, Bertics PJ, Wiepz GJ, Parrill AL, Rodrigues PJ, Lothstein L, Israel M, Sweatman TW. Protein kinase C inhibition by N-benzyladriamycin-14-valerate (AD 198): Structural requirements, isoform specificity and interaction with the C1-regulatory domain. Molec. Cancer Ther. 1:483-492, 2002.
Lothstein L, Israel M, Sweatman TW. Anthracycline targeting: Nuclear versus cytoplasmic-A fork in the road. Drug Resistance Updates. 4:1-9, 2001.
Roaten JB, Kazanietz MG, Sweatman, TW, Lothstein L, Israel M, Parrill AL. Molecular Models of Protein Kinase C-d. J. Med. Chem. 44: 1028-1034, 2001.
Lothstein L, Suttle DP, Roaten JR, Koseki Y, Israel M, Sweatman TW. Catalytic inhibition of topoisomerase II by N-Benzyladriamycin (AD 288). Biochem. Pharmacol. 60: 1621-1628, 2000.
Pawlik CA, Israel M, Sweatman TW, Lothstein L. Multifactorial resistance to the novel hybrid drug 2-chloroethyl-nitrosoureidodaunorubicin (AD 312) in murine and human tumor cells. Oncology Res. 10: 209-218, 1998.
Lothstein L, Rodrigues PJ, Sweatman TW, Israel M. Intracellular activity, distribution, and metabolism of N-Benzyladriamycin-14-valerate (AD 198) are modulated by changes in 14-O-acyl chain length. Anti-Cancer Drugs 9: 58-66, 1998.
Lampidis TJ, Kolonias D, Podona T, Israel M., Safa AR, Lothstein L, Savaraj N, Tapiero H, Priebe W. Circumvention of P-gp MDR as a function of anthracycline lipophilicity and charge. Biochemistry 36: 2679-2685, 1997.
Laboratory roster
Mila Savranskaya Senior Research Assistant
lsavranskaya@utmem.edu