Anti-cancer potential of synergistic phytochemical combinations is influenced by the genetic profile of prostate cancer cell lines

Carol A Gano; Shadma Fatima; Timothy W Failes; Gregory M Arndt; Mila Sajinovic; David Mahns; Ahmad Saedisomeolia; Jens R Coorssen; Joseph Bucci; Paul de Souza; Fatemeh Vafaee; Kieran F Scott

doi:10.3389/fnut.2023.1119274

Anti-cancer potential of synergistic phytochemical combinations is influenced by the genetic profile of prostate cancer cell lines

Front Nutr. 2023 Mar 7:10:1119274. doi: 10.3389/fnut.2023.1119274. eCollection 2023.

Authors

Carol A Gano¹, Shadma Fatima^{1

2

3}, Timothy W Failes⁴, Gregory M Arndt^{4

5}, Mila Sajinovic², David Mahns¹, Ahmad Saedisomeolia⁶, Jens R Coorssen⁷, Joseph Bucci⁸, Paul de Souza^{1

2}, Fatemeh Vafaee^{3

9}, Kieran F Scott^{1

2}

Affiliations

¹ School of Medicine, Western Sydney University, Campbelltown, NSW, Australia.
² Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia.
³ School of Biotechnology and Biological Sciences, UNSW Sydney, Sydney, NSW, Australia.
⁴ ACRF Drug Discovery Centre, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
⁵ School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
⁶ School of Human Nutrition, McGill University, Sainte Anne-de-Bellevue, QC, Canada.
⁷ Departments of Health Sciences and Biological Sciences, Faculties of Applied Health Science, and Mathematics and Science, Brock University, St. Catharines, ON, Canada.
⁸ St George Hospital Clinical School, UNSW, Kogarah, NSW, Australia.
⁹ UNSW Data Science Hub (uDASH), UNSW Sydney, Sydney, NSW, Australia.

Abstract

Introduction: Despite strong epidemiological evidence that dietary factors modulate cancer risk, cancer control through dietary intervention has been a largely intractable goal for over sixty years. The effect of tumour genotype on synergy is largely unexplored.

Methods: The effect of seven dietary phytochemicals, quercetin (0-100 μM), curcumin (0-80 μM), genistein, indole-3-carbinol (I3C), equol, resveratrol and epigallocatechin gallate (EGCG) (each 0-200 μM), alone and in all paired combinations om cell viability of the androgen-responsive, pTEN-null (LNCaP), androgen-independent, pTEN-null (PC-3) or androgen-independent, pTEN-positive (DU145) prostate cancer (PCa) cell lines was determined using a high throughput alamarBlue^® assay. Synergy, additivity and antagonism were modelled using Bliss additivism and highest single agent equations. Patterns of maximum synergy were identified by polygonogram analysis. Network pharmacology approaches were used to identify interactions with known PCa protein targets.

Results: Synergy was observed with all combinations. In LNCaP and PC-3 cells, I3C mediated maximum synergy with five phytochemicals, while genistein was maximally synergistic with EGCG. In contrast, DU145 cells showed resveratrol-mediated maximum synergy with equol, EGCG and genistein, with I3C mediating maximum synergy with only quercetin and curcumin. Knockdown of pTEN expression in DU145 cells abrogated the synergistic effect of resveratrol without affecting the synergy profile of I3C and quercetin.

Discussion: Our study identifies patterns of synergy that are dependent on tumour cell genotype and are independent of androgen signaling but are dependent on pTEN. Despite evident cell-type specificity in both maximally-synergistic combinations and the pathways that phytochemicals modulate, these combinations interact with similar prostate cancer protein targets. Here, we identify an approach that, when coupled with advanced data analysis methods, may suggest optimal dietary phytochemical combinations for individual consumption based on tumour molecular profile.Graphical abstract.

Keywords: Bliss; network pharmacology; pTEN loss; phytochemicals; prostate cancer; synergistic combinations.