Cardiotonic steroids-mediated targeting of the Na(+)/K(+)-ATPase to combat chemoresistant cancers

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Conventional chemotherapy often fails due to cancer cell resistance and multidrug resistance (MDR).
• Targeting overexpressed ion channels and pumps in cancer cells offers a novel therapeutic strategy.
• The alpha subunits of the Na(+)/K(+)-ATPase (sodium pump) are implicated as potential therapeutic targets.

Purpose of the Study:

• To conduct an in-depth structure-activity relationship (SAR) analysis of cardiotonic steroids (CS) targeting sodium pump alpha subunits.
• To evaluate the anticancer effects of cardenolides versus bufadienolides.
• To present pharmacological data on cardenolides for treating cancers with poor prognoses.

Main Methods:

• Review of existing literature on CS, sodium pump alpha subunits, and cancer.
• Analysis of structure-activity relationships (SAR) for cardenolides and bufadienolides.
• Compilation of in vitro, in vivo, pre-clinical, and clinical trial data.

Main Results:

• Specific sodium pump alpha subunits (alpha-1 and alpha-3) are overexpressed in various cancers like NSCLC, GBM, melanoma, kidney, and colon cancers.
• CS, including cardenolides and bufadienolides, demonstrate anticancer effects by targeting these subunits.
• SAR analysis provides insights for designing potent anticancer CS with potentially lower cardiotoxicity.

Conclusions:

• Targeting sodium pump alpha subunits with CS represents a promising strategy against chemotherapy-resistant cancers.
• Further understanding of CS SAR is crucial for developing effective and safe anticancer therapies.
• Cardenolides show potential in combating cancers with dismal prognoses, supported by pre-clinical and clinical data.