Prolonged weightlessness affects promyelocytic multidrug resistance

Area of Science:

• Cell Biology
• Space Medicine
• Pharmacology

Background:

• Multidrug resistance (MDR) in leukocytes poses challenges for cancer therapy.
• Understanding how environmental factors like microgravity affect drug resistance is crucial for astronaut health and potential extraterrestrial medical treatments.

Purpose of the Study:

• To investigate the impact of microgravity on doxorubicin uptake in HL60 and HL60/AR (anthracycline-resistant) promyelocytic leukemia cells.
• To determine if microgravity influences the mechanisms of multidrug resistance in leukocytes.

Main Methods:

• Cultured HL60 and HL60/AR cells were exposed to microgravity aboard the Space Shuttle Endeavour and compared to ground controls.
• Cells were treated with doxorubicin, fixed, and analyzed using confocal microscopy to assess cell structure, drug distribution, and microtubule polymerization.
• Image analysis quantified doxorubicin presence in flight versus ground control cells.

Main Results:

• Microgravity caused a lack of cytoskeletal polymerization, leading to an amorphic cell shape in flight cells.
• Doxorubicin distribution differed, with fewer vesicles in flight cells compared to ground controls.
• Significantly higher doxorubicin accumulation was observed in microgravity-exposed cells (85%) versus ground controls (43%).

Conclusions:

• Microgravity alters leukocyte cell structure, specifically impacting the cytoskeleton.
• Changes in cytoskeletal polymerization under microgravity may affect P-glycoprotein function, a key efflux pump in multidrug resistance.
• These findings suggest microgravity can enhance doxorubicin uptake, potentially modulating multidrug resistance in leukemia cells.