Metronomic Administration of Topotecan Alone and in Combination with Docetaxel Inhibits Epithelial–mesenchymal Transition in Aggressive Variant Prostate Cancers

Abstract

Prostate cancer (PCa) is the second leading cause of non-cutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and radiation therapy remain the primary treatment for early-stage PCa patients (castration-sensitive: CSPC). Following ADT, many patients ultimately develop metastatic castration-resistant PCa (mCRPC). Standard chemotherapy options for CRPC are Docetaxel (DTX) and Cabazitaxel (CBZ), which increase median survival, although the development of resistance is common. Cancer-stem-like cells possess mesenchymal phenotypes (EMT) and play crucial roles in tumor initiation and progression of mCRPC. We have shown that low-dose continuous administration of topotecan (METRO-TOPO) inhibits PCa growth by interfering with key cancer-pathway genes. This study utilized bulk and single-cell or whole-transcriptome analysis (RNA-sequencing and scRNAseq), and we observed greater expression of several EMT markers, including VIM, HAS3, S100A6, TGFB1, CD44, CD55, and CD109 in European American and African American aggressive variant PCa (AVPC) subtypes - mCRPC, neuroendocrine variant (NEPC), and taxane-resistant. The taxane-resistant gene FSCN1 was also expressed highly in single-cell sub-clonal populations in mCRPC. Further, metronomic-topotecan single-agent and combinations with DTX downregulated these EMT markers as well as CD44+ and CD44+/CD133+ “stem-like” cell populations. A microfluidic chip-based cell invasion assay revealed that METRO-TOPO treatment as a single-agent or in combination with DTX was potentially effective against invasive PCa spread. Our RNAseq and scRNAseq analysis were supported by in silico and in vitro studies, suggesting METRO-TOPO combined with DTX may inhibit oncogenic progression by reducing cancer stemness in AVPC through the inhibition of EMT markers and multiple oncogenic factors/pathways.

Metronomic chemotherapy in cancer treatment: new wine in an old bottle

“…In addition, the metronomic application of several chemotherapeutics has been found to inhibit the EMT process in cancer cells 75 , 76 . Single-cell RNA-seq and RNA-seq analysis have indicated that metronomic topotecan treatment induced the downregulation of EMT markers, including CD55 and HAS3, in metastatic castration-resistant prostate cancer 76 .…”

“…In addition, the metronomic application of several chemotherapeutics has been found to inhibit the EMT process in cancer cells 75 , 76 . Single-cell RNA-seq and RNA-seq analysis have indicated that metronomic topotecan treatment induced the downregulation of EMT markers, including CD55 and HAS3, in metastatic castration-resistant prostate cancer 76 . A preclinical study revealed that metronomic cordycepin upregulated E-cadherin and downregulated N-cadherin protein expression in a human oral squamous cell carcinoma xenograft model, which suggests the EMT process was inhibited 75 .…”

Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses

“…Consequently, researchers have developed selective inhibitors for both TOPO I and TOPO II, which have been employed in treating various cancers. For instance, FDA-approved TOPO I inhibitors camptothecin and topotecan decreased the colon, lung, prostate, and melanoma cancer cell development both in in vitro and in clinical trials. − Additionally, TOPO II inhibitors such as etoposide and doxorubicin, also approved by the FDA, are currently used for lung, breast, ovarian, and prostate cancer treatment. − Although selective topoisomerase inhibitors are effective in decreasing prostate cancer cell progression, the compounds have several side effects including hematological toxicity, diarrhea, and neutropenia . Moreover, inhibiting one type of topoisomerase might inadvertently enhance the activity of the other, leading to drug resistance. , Regarding this, dual inhibition of both TOPO I and TOPO II has emerged as a promising strategy to counter the simultaneous increase in topoisomerase activity and to prevent drug resistance.…”