Targeting multidrug resistance-associated protein 1 (MRP1)-expressing cancers: Beyond pharmacological inhibition

Resistance to chemotherapy remains one of the most significant obstacles to successful cancer treatment. While inhibiting drug efflux mediated by ATP-binding cassette (ABC) transporters is a seemingly attractive and logical approach to combat multidrug resistance (MDR), small molecule inhibition of ABC transporters has so far failed to confer clinical benefit, despite considerable efforts by medicinal chemists, biologists, and clinicians. The long-sought treatment to eradicate cancers displaying ABC transporter overexpression may therefore lie within alternative targeting strategies. When aberrantly expressed, the ABC transporter multidrug resistance-associated protein 1 (MRP1, ABCC1) confers MDR, but can also shift cellular redox balance, leaving the cell vulnerable to select agents. Here, we explore the physiological roles of MRP1, the rational for targeting this transporter in cancer, the development of small molecule MRP1 inhibitors, and the most recent developments in alternative therapeutic approaches for targeting cancers with MRP1 overexpression. We discuss approaches that extend beyond simple MRP1 inhibition by exploiting the collateral sensitivity to glutathione depletion and ferroptosis, the rationale for targeting the shared transcriptional regulators of both MRP1 and glutathione biosynthesis, advances in gene silencing, and new molecules that modulate transporter activity to the detriment of the cancer cell. These strategies illustrate promising new approaches to address multidrug resistant disease that extend beyond the simple reversal of MDR and offer exciting routes for further research

Enhanced three-minute oscillation above a sunspot during a solar flare

Three-minute oscillations are a common phenomenon in the solar chromosphere above a sunspot. Oscillations can be affected by the energy release process related to solar flares. In this paper, we report on an enhanced oscillation in flare event SOL2012-07-05T21:42 with a period of around three minutes, that occurred at the location of a flare ribbon at a sunspot umbra-penumbra boundary, and was observed both in chromo-spheric and coronal passbands. An analysis of this oscillation was carried out using simultaneous ground-based observations from the Goode Solar Telescope (GST) at the Big Bear Solar Observatory (BBSO) and space-based observations from the Solar Dynamics Observatory (SDO). A frequency shift was observed before and after the flare, with the running penumbral wave that was present with a period of about 200 s before the flare co-existing with a strengthened oscillation with a period of 180 s at the same locations after the flare. We also found a phase difference between different passbands, with the oscillation occurring from high-temperature to low-temperature passbands. Theoretically, the change in frequency is strongly dependent on the variation of the inclination of the magnetic field and the chromospheric temperature. Following an analysis of the properties of the region, we find the frequency change is caused by the slight decrease of the magnetic inclination angle to the local vertical. In addition, we suggest that the enhanced three-minute oscillation is related to the additional heating, maybe due to the downflow, during the EUV late phase of the flare

Observations of The Magnetic Reconnection Signature of An M2 Flare on 2000 March 23

Multi-wavelength observations of an M 2.0 flare event on 2000 March 23 in NOAA active region 8910 provide us a good chance to study the detailed structure and dynamics of the magnetic reconnection region. In the process of the flare, extreme ultraviolet (EUV) loops displayed two times of sideward motions upon a loop-top hard X-ray source with average velocities of 75 and 25.6 km/s, respectively. We consider these two motions to be the observational evidence of reconnection inflow, and find an X-shaped structure upon the post-flare loops during the period of the second motion. Two separations of the flare ribbons are associated with these two sideward motions, with average velocities of 3.3 and 1.3 km/s, separately. Using the observation of photospheric magnetic field, the velocities of the sideward motions and the separations, we deduce the corresponding coronal magnetic field strength to be about 13.2-15.2 G, and estimate the reconnection rates to be 0.05 and 0.02 for these two magnetic reconnection processes, respectively. We also observe motions of bright points upward and downward along the EUV loops with velocities ranging from 45.4 to 556.7 km/s. A cloud of bright material flowing outward from the loop-top hard X-ray source with an average velocity of 51 km/s in the process of the flare may be accelerated by the tension force of the newly reconnected magnetic field lines. All the observations can be explained by schematic diagrams of magnetic reconnection.Comment: 19 pages, 6 figures, accepted by Ap

GSH facilitates the binding and inhibitory activity of novel multidrug resistance protein 1 (MRP1) modulators

MRP1 (ABCC1) is a membrane transporter that confers multidrug resistance in cancer cells by exporting chemotherapeutic agents, often in a reduced glutathione (GSH)-dependent manner. This transport activity can be altered by compounds (modulators) that block drug transport while simultaneously stimulating GSH efflux by MRP1. In MRP1-expressing cells, modulator-stimulated GSH efflux can be sufficient to deplete GSH and increase sensitivity to chemotherapy, enhancing cancer cell death. Further development of clinically useful MRP1 modulators requires a better mechanistic understanding of modulator binding and its relationship to GSH binding and transport. Here, we explore the mechanism of two MRP1 small molecule modulators, 5681014 and 7914321, in relation to a bipartite substrate-binding cavity of MRP1. Binding of these modulators to MRP1 was dependent on the presence of GSH but not its reducing capacity. Accordingly, the modulators poorly inhibited organic anion transport by K332L-mutant MRP1, where GSH binding and transport is limited. However, the inhibitory activity of the modulators was also diminished by mutations that limit E217βG but spare GSH-conjugate binding and transport (W553A, M1093A, W1246A), suggesting overlap between the E217βG and modulator binding sites. Immunoblots of limited trypsin digests of MRP1 suggest that binding of GSH, but not the modulators, induces a conformation change in MRP1. Together, these findings support the model, in which GSH binding induces a conformation change that facilitates binding of MRP1 modulators, possibly in a proposed hydrophobic binding pocket of MRP1. This study may facilitate the structure-guided design of more potent and selective MRP1 modulators

Conjugate Hard X-ray Footpoints in the 2003 October 29 X10 Flare: Unshearing Motions, Correlations, and Asymmetries

We present a detailed imaging and spectroscopic study of the conjugate hard X-ray (HXR) footpoints (FPs) observed with RHESSI in the 2003 October 29 X10 flare. The double FPs first move toward and then away from each other, mainly parallel and perpendicular to the magnetic neutral line, respectively. The transition of these two phases of FP unshearing motions coincides with the direction reversal of the motion of the loop-top (LT) source, and with the minima of the estimated loop length and LT height. The FPs show temporal correlations between HXR flux, spectral index, and magnetic field strength. The HXR flux exponentially correlates with the magnetic field strength, which also anti-correlates with the spectral index before the second HXR peak's maximum, suggesting that particle acceleration sensitively depends on the magnetic field strength and/or reconnection rate. Asymmetries are observed between the FPs: on average, the eastern FP is 2.2 times brighter in HXR flux and 1.8 times weaker in magnetic field strength, and moves 2.8 times faster away from the neutral line than the western FP; the estimated coronal column density to the eastern FP from the LT source is 1.7 times smaller. The two FPs have marginally different spectral indexes. The eastern-to-western FP HXR flux ratio and magnetic field strength ratio are anti-correlated only before the second HXR peak's maximum. Neither magnetic mirroring nor column density alone can explain the totality of these observations, but their combination, together with other transport effects, might provide a full explanation. We have also developed novel techniques to remove particle contamination from HXR counts and to estimate effects of pulse pileup in imaging spectroscopy, which can be applied to other RHESSI flares in similar circumstances.Comment: 22 pages, 14 figures, 4 tables; ApJ 2009, in pres

Superficial simplicity of the 2010 El Mayor–Cucapah earthquake of Baja California in Mexico

The geometry of faults is usually thought to be more complicated at the surface than at depth and to control the initiation, propagation and arrest of seismic ruptures. The fault system that runs from southern California into Mexico is a simple strike-slip boundary: the west side of California and Mexico moves northwards with respect to the east. However, the M_w 7.2 2010 El Mayor–Cucapah earthquake on this fault system produced a pattern of seismic waves that indicates a far more complex source than slip on a planar strike-slip fault. Here we use geodetic, remote-sensing and seismological data to reconstruct the fault geometry and history of slip during this earthquake. We find that the earthquake produced a straight 120-km-long fault trace that cut through the Cucapah mountain range and across the Colorado River delta. However, at depth, the fault is made up of two different segments connected by a small extensional fault. Both segments strike N130° E, but dip in opposite directions. The earthquake was initiated on the connecting extensional fault and 15 s later ruptured the two main segments with dominantly strike-slip motion. We show that complexities in the fault geometry at depth explain well the complex pattern of radiated seismic waves. We conclude that the location and detailed characteristics of the earthquake could not have been anticipated on the basis of observations of surface geology alone

Enhanced three-minute oscillation above a sunspot during a solar flare

Three-minute oscillations are a common phenomenon in the solar chromosphere above a sunspot. Oscillations can be affected by the energy release process related to solar flares. In this paper, we report on an enhanced oscillation in flare event SOL2012-07-05T21:42 with a period of around 3 minutes that occurred at the location of a flare ribbon at a sunspot umbral–penumbral boundary and was observed in both chromospheric and coronal passbands. An analysis of this oscillation was carried out using simultaneous ground-based observations from the Goode Solar Telescope at the Big Bear Solar Observatory and space-based observations from the Solar Dynamics Observatory. A frequency shift was observed before and after the flare, with the running penumbral wave that was present with a period of about 200 s before the flare coexisting with a strengthened oscillation with a period of 180 s at the same locations after the flare. We also found a phase difference between different passbands, with the oscillation occurring from high-temperature to low-temperature passbands. Theoretically, the change in frequency was strongly dependent on the variation of the inclination of the magnetic field and the chromospheric temperature. Following an analysis of the properties of the region, we found the frequency change was caused by a slight decrease of the magnetic inclination angle with respect to the local vertical. In addition, we suggest that the enhanced 3 minute oscillation was related to the additional heating, maybe due to the downflow, during the EUV late phase of the flare

Quark initiated coherent diffractive production of muon pair and W boson at hadron colliders

The large transverse momentum muon pair and W boson productions in the quark initiated coherent diffractive processes at hadron colliders are discussed under the framework of the two-gluon exchange parametrization of the Pomeron model. In this approach, the production cross sections are related to the small-x off-diagonal gluon distribution and the large-x quark distribution in the proton (antiproton). By approximating the off-diagonal gluon distribution by the usual gluon distribution function, we estimate the production rates of these processes at the Fermilab Tevatron.Comment: 11pages, 6 PS figures, to appear in PR