A natural compound screen identified several anticancer compounds, among which azapodophyllotoxin (AZP) was found to be the most potent. AZP caused decreased viability of both mouse and human lymphoma and renal cell cancer (RCC) tumor-derived cell lines. Novel AZP derivatives were synthesized and screened identifying compound NSC750212 to inhibit the growth of both lymphoma and RCC both in vitro and in vivo. A nanoimmunoassay was used to assess the NSC750212 mode of action in vivo. On the basis of the structure of AZP and its mode of action, AZP disrupts tubulin polymerization. Through desorption electrospray ionization mass spectrometry imaging, NSC750212 was found to inhibit lipid metabolism. NSC750212 suppresses monoglycerol metabolism depleting lipids and thereby inhibits tumor growth. The dual mode of tubulin polymerization disruption and monoglycerol metabolism inhibition makes NSC750212 a potent small molecule against lymphoma and RCC.
Bibliographical noteFunding Information:
We thank current and former members of the Felsher, Malhotra, and Zare laboratories for their helpful suggestions during this project. We thank B. Rosellini and R. Barros for their help. We are very grateful for the SPARK program advisors, especially Dr. S. Schow and Dr. R. Greenhouse. A.M.G. and D.W.F. are grateful for the support of Stanford’s SPARK Translational Research Program, Stanford Clinical and Translational Science Award (CTSA) program and Spectrum (UL1TR003142). A.M.G. and K.M. are grateful to the Stanford Cancer Translational Nanotechnology Training (TNT) T32 training grant funded by the National Cancer Institute (T32 CA196585) and the Stanford Center of Molecular Analysis and Design, respectively. A.R. is thankful to the Stanford Clinical and Translational Science Award (CTSA) for T32 training grant funded by the National Center for Advancing Translational Sciences (NCATS). This work is supported by the National Institutes of Health under R01 CA184384 (D.W.F. and R.N.Z.), U01 CA188383 (D.W.F.), R01 CA208735 PQ7 (D.W.F.), R35CA253180 (D.W.F.), and R01 DK114174 (S.V.M.).
© 2022 American Chemical Society. All rights reserved.
- Kidney Cancer