Phospholipid scramblases (PLSCRs) that catalyze rapid mixing of plasma membrane lipids result in surface exposure of phosphatidyl serine (PS), a lipid normally residing to the inner plasma membrane leaflet. PS exposure provides a chemotactic eat-me signal for phagocytes resulting in non-inflammatory clearance of apoptotic cells by efferocytosis. However, metastatic tumor cells escape efferocytosis through alteration of tumor microenvironment and apoptotic signaling. Tumor cells exhibit altered membrane features, high constitutive PS exposure, low drug permeability and increased multidrug resistance through clonal evolution. PLSCRs are transcriptionally up-regulated in tumor cells leading to plasma membrane remodeling and aberrant PS exposure on cell surface. In addition, PLSCRs interact with multiple cellular components to modulate cancer progression and survival. While PLSCRs and PS exposed on tumor cells are novel drug targets, many exogenous molecules that catalyze lipid scrambling on tumor plasma membrane are potent anticancer therapeutic molecules. In this review, we provide a comprehensive analysis of scramblase mediated signaling events, membrane alteration specific to tumor development and possible therapeutic implications of scramblases and PS exposure.
An amphiphilic phytochemical
fraction isolated from methanol extract
of
Gymnema sylvestre
leaf powder contained
six terpenoids, two flavonoids, and one alkaloid that induced rapid
flip-flop of fluorescent phospholipid analog in the phosphatidyl choline
bilayer. Lipid-flipping activity of the methanol-extracted fraction
of
G. sylvestre
(MEFGS) was dose-dependent
and time-dependent with a rate constant
k
= (12.09
± 0.94) mg
–1
min
–1
that was
saturable at (40 ± 1) % flipping of the fluorescent lipid analogue.
Interactions of MEFGS phytochemicals with large unilamelar vesicles
led to time-dependent change in their rounded morphology into irregular
shapes, indicating their membrane-destabilizing activity. MEFGS exhibited
antibacterial activity on
Escherichia coli
(MTCC-118),
Staphylococcus aureus
(MTCC-212), and
Pseudomonas aeruginosa
(MTCC-1035) with IC
50
values 0.5, 0.35, and 0.1 mg/mL,
respectively. Phytochemicals in MEFGS increased membrane permeabilization
in all three bacteria, as indicated by 23, 17, and 17% increase in
the uptake of crystal violet, respectively. MEFGS enhanced membrane
damage, resulting in a 3–5 fold increase in leakage of cytosolic
ions, 0.5–2 fold increase in leakage of PO
4
–
, and 15–20% increase in loss of cellular proteins.
MEFGS synergistically increased the efficacy of curcumin, amoxillin,
ampicillin, and cefotaxime on
S. aureus
probably by enhancing their permeability into the bacterium. For
the first time, our study reveals that phytochemicals from
G. sylvestre
enhance the permeability of the bacterial
plasma membrane by facilitating flip-flop of membrane lipids. Lipid-flipping
phytochemicals from
G. sylvestre
can
be used as adjuvant therapeutics to enhance the efficacy of antibacterials
by increasing their bioavailability in the target bacteria.
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