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Conserved molecular mechanisms
underlying the effects of
small molecule chemotherapeutics
on cellsHEMANT SARIN, MD,
MScPH, ISTP
Why is it necessary to interrogate the conserved
biophysical properties of small molecule chemotherapies?
•Clinical efficacy remains questionable for the treatment of solid and hematopoietic malignancies
•Solid tumors in particular, for purposes of improving the tumor tissue selectiveness of enhanced permeation and retention (EPR)-based chemotherapy attached to optimally-sized nanoparticles
•Optimally-sized imageable dendrimer nanoparticle-based small molecule chemotherapy at ~9 nanometers (Hydrodynamic diameter = Dehydrated Diameters for such NPs)
•Sarin H: Effective transvascular delivery of chemotherapy into cancer cells with imageable nanoparticles in the 7 to 10 nanometer size range (Chapter 2). In: Current Advances in the Medical Application of Nanotechnology. Bentham Science Publishers Ltd.; 2012: 10-24
•Sarin, H. On the future development of optimally-sized lipid-insoluble systemic therapies for CNS solid tumors and other neuropathologies. Recent Patents on CNS Drug Discovery, 5 (3): 239-252, 2010
Traditional mechanisms of small molecule
chemotherapeutics based on:•Naked Target
–On protein receptor/enzyme in isolation, which provides information on relative binding affinities for intra-cellular proteins
•Cellular level in vitro–Provides information on the inhibitory concentrations needed to achieve tumor cell death and the overexpression status of induced pro- or anti-apoptotic protein forms
–But does not take into consideration cell membrane (CM) phospholipid or CM protein receptor interactions
Traditional mechanisms of small molecule
chemotherapeutics based on:•Systemic level in vivo
–Gives an idea of the dosing range necessary to achieve chemotherapeutic effect and tumor regression
INCOMPLETE INFORMATION:
On the modes, the levels and the character of interactions of
small biomolecules with cell membrane (CM) constituents
and at the intra-cellular levels
For the proper determination of the apoptotic potential of chemoxenobiotics at the
cellular level , important to know whether:•With and across cell membrane (CM) protein aqueous channels
•With CM surface protein receptors and endocytic
•With CM surface protein receptors and non-endocytic
•Directly with CM phospholipids themselves (if not across pores AND if not with CM surface protein receptors
For the proper determination of the apoptotic potential of
chemoxenobiotics at the sub-cellular level ,
important to know whether:•Nuclear, mitochondrial or mictroubular
•Mitochondrial
•Microtubular
•Non-microtubular (ie FKBP12/Inter-Domain (I-II/III) of FKBP52)
The conserved biophysical properties
of small molecule chemotherapeutics that predict the modes, the
levels and the character of interactions of small
biomolecules with CM constituents & at the intra-cellular levels
•Predicted chemoxenobiotic structure (2-D)
•Predicted molecular size (vdWD; nm)•Predicted internal (Core) lipophilicity (nm-1)
•Predicted external/peripheral hydrophilicity (nm-1) AND distribution over molecular space –Charge (Cationic or Anionic), Hydroxylation, Carbonylation, Etheroylation & Carboxylation
Small Molecule Chemoxenobiotic
Classification I•Pure Hydrophiles
Defined as xenobiotics with: (1) Insufficient (IS) intervening lipophilicity
(2) A hydrophilic (-) Log OWPC-to-vdWD ratio (nm-1 ) at physiologic of pH 7.4
-- Non-charged pure hydrophiles being CM aqueous channel pore permeable at vdWDs <0.78 nm and intra-cellularly localizing
Small Molecule Chemoxenobiotic Classification IIA•Hydro-lipophiles
Defined as xenobiotics with: (1) Sufficient (S) intervening lipophilicity (Log incorpOWPC-to-vdWD (nm-1 )
(2) A hydrophilic (-) Log OWPC-to-vdWD ratio (nm-1 ) at physiologic of pH 7.4
-- CM aqueous channel pore impermeable, and interaction, instead, with CM non-channel receptor, or CM receptor interaction
Small Molecule Chemoxenobiotic Classification IIB• Hydro-lipophiles
(A) Di-carboxylated (IS 1+ 1- S 0) Non-Channel Folic Acid Receptor-Mediated CM Endocytosis
(B) Non-Cationic (0), Mono-Cationic (S 1+ 0) or Di-Cationic (1+ S 1+)
Polyhydroxylated / Carbonylated / Etheroylated Channel Receptor -Mediated CM Endocytosis
(ie Na+/K+ ATPase; Ca2+ Channel)
(C) Di-Cationic (1+ IS 1+: 2+) Non-Channel Receptor -Mediated CM
Endocytosis
Small Molecule Chemoxenobiotic Classification IIIA•Lipophiles
Defined as xenobiotics with:
(1) Non-charged less lipophilic Toxicants with vdWDs <0.78 nm (CM channel pore permeable sub-CM interactors): Overall lipophilicity [(+) Log OWPC-to-vdWD ratio (nm-1 )]
AND (2) Xenobiotics with vdWDs >0.78 nm: Overall
lipophilicity [(+) Log OWPC-to-vdWD ratio (nm-1 )] with sufficient (S) intervening lipophilicity (Log incorpOWPC-to-vdWD; nm-1 ) in the presence of molecular hydrophilicity (Monohydroxylation / Monocarbonylated / Monoetheroylated / Monocarboxylated; Polyhydroxylated / Polycarbonylated / Polyetheroylated; Charge)
-- > (+) Overall Log OWPC-to-vdWD ratio (nm-1 )
Small Molecule Chemoxenobiotic Classification IIIA•Lipophiles
Sub-classes of Xenobiotics with vdWDs >0.78 nm and Overall lipophilicity [(+) Log OWPC-to-vdWD ratio (nm-1 )] with sufficient (S) intervening lipophilicity (Log incorpOWPC-to-vdWD; nm-1 ) in the presence of molecular hydrophilicity (Monohydroxylation / Monocarbonylated / Monoetheroylated / Monocarboxylated; Polyhydroxylated / Polycarbonylated / Polyetheroylated; Charge)
(1) Present isotropically [CM receptor hydrophobic core interactors
with vdWDs >0.78 nm (Receptor-Mediated CM Endocytosis)]
OR (2) Present anisotropically [CM Cholesterol /
phospholipid Glycerol-to-fatty acid-ester or CM receptor
hydrophobic core interactors with vdWDs >0.78 nm (potential for CM perturbomodulation)]
Small Molecule Chemoxenobiotic Classification IIIC• Lipophiles
(A) Anionic (S 1- 0) with Linear Structure, Cataniononeutral (IS 1+ 1- S 0) with Linear Structure, Anisotropic Polyneutral (S 0 0) with Linear Structure, Isotrophic Polyneurral with Linear or Compact Structure: CM Cholesterol or CM phospholipid Glycerol-to-fatty acid- ester Interaction or Disruption
(B) Cationic Isotrophic Polyneutral (0 S 1+ 0) with Flexible Linear Structure: Channel Receptor -Mediated CM Endocytosis (Ca2+ Channel: ie Verapamil)
(C) Cationic Less Isotrophically Polyneutral (0 S 1+ 0) with Compact Structure: Channel Receptor Obstruction without Endocytosis (Ca2+ Channel: ie Quinidine, a P-glycoprotein potential inducer) (D) Anisotrophic Polyneutral (S 0 0) with Compact Linear Structure: (Non-Channel) P-glycoprotein Receptor Binding without Endocytosis (ie Artemisinin: Sin Qua Non P-gp Inducer)
(E) Isotrophic Polyneurral (S 0 0) with Non-Linear Non-Compact Structure: Non-Channel Receptor-Mediated CM Endocytosis
(F) Di-neutral/Polyneutral Sterol with Non-Linear Compact Structure: Non-Channel Receptor-Mediated Pressuromodulation Antagonism (ie Sex Steroid Receptor Antagonists)
Nitroso-N-methylurea (MNU)
Temozolamide (TMZ)
Nitroso-N-ethylurea (ENU)
Cell Membrane (CM) Channel Aqueous Pore Permeation and DNA/RNA Adduction
Cell Membrane (CM) Channel Aqueous Pore Permeation and Nucleoside Substitution
Decitabine
5-Fluorouracil (5-FU)
3-Methyladenine
Gemcitabine
Cell Membrane (CM) Channel Aqueous Pore Permeation with the Potential to Bind to Cytochrome P450s: DNA Adduction and/or Crosslinking
Procarbazine
Carmustine (BCNU)
Cyclophosphamide
Cell Membrane (CM) Insertoassociation and Phospholipid Interspace Widening with Potential for 1ary Indirect Pressuromodulation
Cyclosporine A
Cell Membrane (CM) Cholesteroloassociation-to-CM Phospholipidoassociation: Cholesterol Removal-to-CM Phospholipid Pertubation and Potential for 1ary Indirect Pressuromodulation
Amphotericin B
Chlorambucil
Melphalan
Ketoconazole
Capecitabine
Fluconazole
Divalent Cationicity-Mediated Cell Membrane (CM) Receptor Vesiculo-Vacuolization Endocytosis, Sub-cellular Vacuolization along with Exosome Formation with Potential for CM Receptor-Mediated 3ary Indirect Shift Pressuromodulation
AMD3100 (Plerixafor)
Paraquat
Bleomycin
Carbonylation/Hydroxylation cum Cationicity-Facilitated Cell Membrane (CM) Channel Endocytosis and Mitochondrial VDAC Association: Non-association of Microtubule Tubulin to Mitochondrial Membrane (MM)
and Mitochondrial Anchorage Non-Mobility-Mediated MM Disruption/Mitochondria-Mediated Apoptosis
Vincristine
Doxorubicin
Dual Carboxylation-Facilitated Cell Membrane (CM) Receptor Endocytosis: Mitochondrial Membrane (MM) and Rough Endoplasmic Reticulum (RER) Membrane (RERM) Vesiculization
Methotrexate
Raltitrexed
Hydroxylation/Carbonylation/Dual Carboxylation-Facilitated Cell Membrane (CM) Receptor Endocytosis: Tubulin Polymerization Re-Polymerization Inhibition and Mitochondria-Mediated Apoptosis
to Rapamycin-Associated Protein Binding Tubulin Non-Binding
Etoposide (VP16)
Teniposide (VM26)
Colchicine
Paclitaxel (Taxol)
Ixabepilone
(+/-) Spiro-oxanthromicin A
Tacrolimus
Cell Membrane (CM) Receptor-Mediated Pressuromodulation Antagonism/Partial Antagonism: Antagonism/Partial Antagonism of Direct CM Receptor-Mediated Pressuromodulation
Hydroxytamoxifen (Afimoxitene)
Abiraterone
Cell Membrane (CM) Receptor-Mediated Antagonism/Partial Antagonism of Pressuromodulation Extracellulomodulation with Concomitant Receptor Kinase Inhibition:
Antagonism/Partial Antagonsim of Direct CM Receptor-Mediated Pressuromodulation +/- External Cationomodulation (>= 3+ -> 1+)
Gefitinib (Iressa)
Ceritinib
Erlotinib (Tarceva)
Lapatinib
MK-2206
Staurosporine
Afatinib
Imatinib
Crizotinib
Hydroxycamptothecin
AMD070
Topotecan
GM
-CS
F R
PD
GF
R
TR
AIL
RT
RA
IL R
Conclusions - I•Based on the observations herein, on the
modes, levels and character of interactions of xenobiotics and chemoxenobiotics with cells, analyzed in terms of the predicted conserved biophysical properties, insight has been gained into the specific mechanisms by which chemoxenobiotics enter cells and the organelles with which they interact to induce cytotoxcity
Conclusions - II•This knowledge is applicable towards
improving the effectiveness of combinationatory small chemotherapy regimens in current clinical use, for the treatment of solid and hematopoietic malignancies, including the order in which chemoxenobiotics are administered in combinationatory treatment regimens, in temporal proximity
Conclusions - III• It is anticipated that by the application of
this study's findings on the modes and character of cellular interactions, existing combinationatory chemotherapy regimens can be designed to be more efficacious, and furthermore, that by the incorporation of this knowledge into the algorithms for the design of personalized cancer treatments, the predictive accuracy of such algorithms can be further optimized
Conclusions - IV•For the curative treatment of solid
malignancies, small molecule chemoxenobiotics must be made to selectively accumulate within the uM in the tumor milieu, where they must remain for prolonged duration in order for uniform tumorocidal cytotoxcity to tumor and tumor-associated cells
Conclusions - IV• For the further translational development of novel
chemotherapeutic regimens employing optimally-sized and -designed biocompatible imageable dendrimer-based nanoparticles bearing labilely-attached small molecule chemoxenobiotics– Optimally-sized imageable dendrimer nanoparticle-
based small molecule chemotherapy at ~9 nanometers (Hydrodynamic diameter = Dehydrated Diameters for such NPs)•Sarin, H. Translational Theranostic Methodology for Diagnostic Imaging and the Concomitant Treatment of Malignant Solid Tumors. Inaugural Issue Neurovascular Imaging, 1(3), 2015